Pyridine derivatives as rearranged during transfection (ret) kinase inhibitors

ABSTRACT

This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

FIELD OF INVENTION

This invention relates to novel compounds which are inhibitors of theRearranged during Transfection (RET) kinase, to pharmaceuticalcompositions containing them, to processes for their preparation, and totheir use in therapy, alone or in combination, for the normalization ofgastrointestinal sensitivity, motility and/or secretion and/or abdominaldisorders or diseases and/or treatment related to diseases related toRET dysfunction or where modulation of RET activity may have therapeuticbenefit including but not limited to all classifications of irritablebowel syndrome (IBS) including diarrhea-predominant,constipation-predominant or alternating stool pattern, functionalbloating, functional constipation, functional diarrhea, unspecifiedfunctional bowel disorder, functional abdominal pain syndrome, chronicidiopathic constipation, functional esophageal disorders, functionalgastroduodenal disorders, functional anorectal pain, inflammatory boweldisease, proliferative diseases such as non-small cell lung cancer,hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer,follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroidcancer, brain tumors, peritoneal cavity cancer, solid tumors, other lungcancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-LindauSyndrome and kidney tumors, breast cancer, fallopian tube cancer,ovarian cancer, transitional cell cancer, prostate cancer, cancer of theesophagus and gastroesophageal junction, biliary cancer andadenocarcinoma, and any malignancy with increased RET kinase activity.

BACKGROUND OF THE INVENTION

Irritable bowel syndrome (IBS) is a common illness affecting 10-20% ofindividuals in developed countries and is characterized by abnormalbowel habits, bloating and visceral hypersensitivity (Camilleri, M., N.Engl. J. Med., 2012, 367:1626-1635). While the etiology of IBS isunknown it is thought to result from either a disorder between the brainand gastrointestinal tract, a disturbance in the gut microbiome orincreased inflammation. The resulting gastrointestinal changes affectnormal bowel transit resulting in either diarrhea or constipation.Furthermore in a majority of IBS patients the sensitization of theperipheral nervous system results in visceral hypersensitivity orallodynia (Keszthelyi, D., Eur. J. Pain, 2012, 16:1444-1454).

While IBS does not directly alter life expectancy it has a considerableeffect on a patient's quality of life. Moreover there is a significantfinancial cost for IBS associated healthcare and lost productivity dueto worker absenteeism (Nellesen, D., et al., J. Manag. Care Pharm.,2013, 19:755-764). One of the most important symptoms that greatlyaffect an IBS patient's quality of life is visceral pain (Spiegel, B.,et al., Am. J. Gastroenterol., 2008, 103:2536-2543). Molecularstrategies that inhibit IBS associated visceral pain would greatlyinfluence the IBS patient's quality of life and reduce associated costs.

Rearranged during transfection (RET) is a neuronal growth factorreceptor tyrosine kinase that is activated upon binding one of fourneurotrophic factors glial cell line-derived neurotrophic factor (GDNF),neurturin, artemin and persephin in combination with a co-receptor GDNFfamily receptor alpha-1, 2, 3, and 4 respectively (Plaza-Menacho, I., etal., Trends Genet., 2006, 22:627-636). RET is known to play an importantrole in the development and survival of afferent nociceptors in the skinand gut. RET kinase knock-out mice lack enteric neurons and have othernervous system anomalies suggesting that a functional RET kinase proteinproduct is required during development (Taraviras, S. et al.,Development, 1999, 126:2785-2797). Moreover population studies ofpatients with Hirschsprung's disease characterized by colonicobstruction due to lack of normal colonic enervation have a higherproportion of both familial and sporadic loss of function RET mutations(Butler Tjaden N., et al., Transl. Res., 2013, 162:1-15).

Similarly, aberrant RET kinase activity is associated with multipleendocrine neoplasia (MEN 2A and 2B), familial medullary thyroidcarcinoma (FMTC), papillary thyroid carcinoma (PTC) and Hirschsprung'sdisease (HSCR) (Borello, M., et al., Expert Opin. Ther. Targets, 2013,17:403-419). MEN 2A is a cancer syndrome resulting from a mutation inthe extracellular cysteine-rich domain of RET leading to dimerizationvia a disulfide bond which causes constitutive activation of thetyrosine kinase activity (Wells Jr, S., et al., J. Clin. Endocrinol.Metab., 2013, 98:3149-3164). Individuals with this mutation may developmedullary thyroid carcinoma (MTC), parathyroid hyperplasia, andpheochromocytoma. MEN 2B is caused by a Met918Thr mutation in RET whichchanges the tyrosine kinase specificity. MEN 2B is similar to MEN 2A,but lacks the parathyroid hyperplasia and also leads to development ofnumerous mucosal ganglia of the lips, tongue, and intestinal tract.Chromosomal rearrangements linking the promoter and NH2-terminal domainsor unrelated gene(s) to the COOH-terminus of RET kinase resulting inconstitutively activated chimeric forms of the receptor (RET/PTC) arethought to be tumor initiating events in PTC (Viglietto, G. et al.,Oncogene, 1995, 11:1207-1210). PTC's encompass about 80% of all thyroidcarcinomas. These data indicate that inhibition of RET may be anattractive therapeutic strategy for the treatment of pain associatedwith IBS and other gastrointestinal disorders and for the treatment ofcancers with constitutive RET kinase activity.

SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I):

wherein:

R¹ is hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, hydroxyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, amino, ((C₁-C₆)alkyl)amino-, or((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino-;

each R² is independently selected from the group consisting of halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, hydroxyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, amino,((C₁-C₆)alkyl)amino-, and ((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino-;

R³ is phenyl or 5- or 6-membered heteroaryl, each of which is optionallysubstituted with one to three substituents independently selected fromhalogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, 5- or6-membered heteroaryl, —OR⁴, and —CONR⁵R⁶; wherein said (C₁-C₆)alkyl isoptionally substituted by cyano, hydroxyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, or —NR⁵R⁶; and wherein said 5- or 6-memberedheteroaryl substituent is optionally substituted by halogen,(C₁-C₄)alkyl, or halo(C₁-C₄)alkyl;

R⁴ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or 4-to 6-membered heterocycloalkyl; wherein said (C₁-C₆)alkyl is optionallysubstituted by cyano, hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, or—NR⁵R⁶; and wherein said (C₃-C₆)cycloalkyl is optionally substitutedwith one or two substituents independently selected from (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, andhalo(C₁-C₄)alkoxy; and wherein said 4- to 6-membered heterocycloalkyl isoptionally substituted with one or two substituents independentlyselected from (C₁-C₄)alkyl and halo(C₁-C₄)alkyl;

R⁵ and R⁶ are each independently selected from the group consisting ofhydrogen, (C₁-C₄)alkyl, and halo(C₁-C₄)alkyl;

or R⁵ and R⁶ taken together with the nitrogen to which they are attachedrepresent a 5- or 6-membered saturated ring, optionally containing anadditional heteroatom selected from oxygen, nitrogen, and sulfur,wherein said ring is optionally substituted by halogen, (C₁-C₄)alkyl, orhalo (C₁-C₄)alkyl; and

n is 0, 1, or 2;

or pharmaceutically acceptable salts thereof.

This invention also relates to a pharmaceutical composition comprising acompound of Formula (I) and a pharmaceutically acceptable excipient.

This invention also relates to a method of treating irritable bowelsyndrome comprising administering to a human in need thereof aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. This invention also relates to a method oftreating cancer comprising administering to a human in need thereof aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

This invention also relates to compounds of Formula (I) for use intherapy. This invention also relates to the use of a compound of Formula(I) or a pharmaceutically acceptable salt thereof for the treatment ofirritable bowel syndrome. This invention also relates to the use of acompound of Formula (I) or a pharmaceutically acceptable salt thereoffor the treatment of cancer.

This invention also relates to the use of a compound of Formula (I) or apharmaceutically acceptable salt thereof in the preparation of amedicament for the treatment of diseases mediated by RET. This inventionalso relates to the use of a compound of Formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of irritable bowel syndrome. This inventionalso relates to the use of a compound of Formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of the Formula (I) orpharmaceutically acceptable salts thereof as defined above.

This invention also relates to compounds of Formula (II):

wherein:

X is N or CR¹⁰;

R¹ is hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, hydroxyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, amino, ((C₁-C₆)alkyl)amino-, or((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino-;

each R² is independently selected from the group consisting of halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, hydroxyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, amino,((C₁-C₆)alkyl)amino-, and ((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino-;

R⁴ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or 4-to 6-membered heterocycloalkyl; wherein said (C₁-C₆)alkyl is optionallysubstituted by cyano, hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, or—NR⁵R⁶; and wherein said (C₃-C₆)cycloalkyl is optionally substitutedwith one or two substituents independently selected from (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, andhalo(C₁-C₄)alkoxy; and wherein said 4- to 6-membered heterocycloalkyl isoptionally substituted with one or two substituents independentlyselected from (C₁-C₄)alkyl and halo(C₁-C₄)alkyl;

R⁵ and R⁶ are each independently selected from the group consisting ofhydrogen, (C₁-C₄)alkyl, and halo(C₁-C₄)alkyl;

or Wand R⁶ taken together with the nitrogen to which they are attachedrepresent a 5- or 6-membered saturated ring, optionally containing anadditional heteroatom selected from oxygen, nitrogen, and sulfur,wherein said ring is optionally substituted by halogen, (C₁-C₄)alkyl, orhalo(C₁-C₄)alkyl;

R⁷ is hydrogen, halogen, or (C₁-C₄)alkoxy; R⁸ is hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, 5- or6-membered heteroaryl, —OR⁴, or —CONR⁵R⁶; wherein said (C₁-C₆)alkyl isoptionally substituted by cyano, hydroxyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, or —NR⁵R⁶; and wherein said 5- or 6-memberedheteroaryl is optionally substituted by halogen, (C₁-C₄)alkyl, orhalo(C₁-C₄)alkyl;

R⁹ is hydrogen, halogen, or halo(C₁-C₄)alkyl;

R¹⁰ is hydrogen, halogen, halo(C₁-C₄)alkyl, or 5- or 6-memberedheteroaryl, wherein said 5- or 6-membered heteroaryl is optionallysubstituted by halogen, (C₁-C₄)alkyl, or halo(C₁-C₄)alkyl; and

n is 0, 1, or 2;

provided that when X is CR¹⁰ at least one of R⁷, R⁸, R⁹, and R¹⁰ ishydrogen;

or pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula(I) or (II) wherein R¹ is fluorine, chlorine, (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, (C₃-C₆)cycloalkoxy, amino,((C₁-C₆)alkyl)amino-, or ((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino-. In anotherembodiment, this invention relates to compounds of Formula (I) or (II)wherein R¹ is (C₁-C₄)alkoxy. In a specific embodiment, this inventionrelates to compounds of Formula (I) or (II) wherein R¹ is ethoxy.

In another embodiment, this invention relates to compounds of Formula(I) or (II) wherein n is 1 or 2 and each R² is independently halogen. Inanother embodiment, this invention relates to compounds of Formula (I)or (II) wherein n is 1 or 2 and each R² is fluorine.

In another embodiment, this invention relates to compounds of Formula(I) wherein R³ is phenyl which is optionally substituted with one tothree substituents independently selected from halogen, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, 5- or 6-membered heteroaryl,—OR⁴, and —CONR⁵R⁶; wherein said (C₁-C₆)alkyl is optionally substitutedby cyano, hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, or —NR⁵R⁶; andwherein said 5- or 6-membered heteroaryl is optionally substituted byhalogen, (C₁-C₄)alkyl, or halo(C₁-C₄)alkyl. In another embodiment, thisinvention relates to compounds of Formula (I) wherein R³ is phenyl whichis optionally substituted with one to three substituents independentlyselected from fluorine, chlorine, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl, cyano,(C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy-, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-,amino(C₂-C₄)alkoxy-, ((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, and —CONH₂; whereinsaid (C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-. In another embodiment, thisinvention relates to compounds of Formula (I) wherein R³ is phenyl whichis optionally substituted with one or two substituents independentlyselected from (C₁-C₄)alkyl and halo(C₁-C₄)alkyl; wherein said(C₁-C₄)alkyl is optionally substituted by cyano or hydroxyl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R³ is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, or triazinyl, each of which is optionally substituted withone to three substituents independently selected from halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano, 5- or6-membered heteroaryl, —OR⁴, and —CONR⁵R⁶; wherein said (C₁-C₆)alkyl isoptionally substituted by cyano, hydroxyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, or —NR⁵R⁶; and wherein said 5- or 6-memberedheteroaryl is optionally substituted by halogen, (C₁-C₄)alkyl, orhalo(C₁-C₄)alkyl. In another embodiment, this invention relates tocompounds of Formula (I) wherein R³ is furanyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, each of which isoptionally substituted with one to three substituents independentlyselected from fluorine, chlorine, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl, cyano,(C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy-, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-,amino(C₂-C₄)alkoxy-, ((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, and —CONH₂; whereinsaid (C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-.

In another embodiment, this invention relates to compounds of Formula(I) wherein R³ is pyridinyl which is optionally substituted with one tothree substituents independently selected from fluorine, chlorine,(C₁-C₆)alkyl, halo(C₁-C₄)alkyl, cyano, (C₁-C₄)alkoxy,hydroxy(C₂-C₄)alkoxy-, (C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, and —CONH₂; whereinsaid (C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-. In another embodiment, thisinvention relates to compounds of Formula (I) wherein R³ is pyridinylwhich is optionally substituted with one or two substituentsindependently selected from (C₁-C₄)alkyl and halo(C₁-C₄)alkyl; whereinsaid (C₁-C₄)alkyl is optionally substituted by cyano or hydroxyl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R³ is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, or triazinyl, each of which is optionally substituted by(C₁-C₄)alkyl or halo(C₁-C₄)alkyl. In another embodiment, this inventionrelates to compounds of Formula (I) wherein R³ is isoxazolyl which isoptionally substituted by (C₁-C₄)alkyl or halo(C₁-C₄)alkyl.

In another embodiment, this invention relates to compounds of Formula(II) wherein R⁷ is hydrogen or halogen. In a specific embodiment, thisinvention relates to compounds of Formula (II) wherein R⁷ is hydrogen orfluorine. In a more specific embodiment, this invention relates tocompounds of Formula (II) wherein R⁷ is hydrogen.

In another embodiment, this invention relates to compounds of Formula(II) wherein R⁸ is hydrogen, fluorine, chlorine, (C₁-C₆)alkyl,halo(C₁-C₄)alkyl, cyano, (C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy-,(C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, or —CONH₂; wherein said(C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-. In another embodiment, thisinvention relates to compounds of Formula (II) wherein R⁸ is hydrogen or(C₁-C₆)alkyl; wherein said (C₁-C₆)alkyl is optionally substituted bycyano, hydroxyl, (C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-. In another embodiment, thisinvention relates to compounds of Formula (II) wherein R⁸ is(C₁-C₄)alkyl which is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-.

In another embodiment, this invention relates to compounds of Formula(II) wherein R⁹ is halo(C₁-C₄)alkyl. In a specific embodiment, thisinvention relates to compounds of Formula (II) wherein R⁹ istrifluoromethyl.

In another embodiment, this invention relates to compounds of Formula(II) wherein X is CR¹⁰ and R¹⁰ is hydrogen, halogen, halo(C₁-C₄)alkyl,furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl, wherein said furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted byhalogen, (C₁-C₄)alkyl, or halo(C₁-C₄)alkyl. In another embodiment, thisinvention relates to compounds of Formula (II) wherein X is CR¹⁰ and R¹⁰is hydrogen, fluorine, chlorine, or trifluoromethyl. In a specificembodiment, this invention relates to compounds of Formula (II) whereinX is CH. In another specific embodiment, this invention relates tocompounds of Formula (II) wherein X is N.

In a particular embodiment, this invention relates to compounds ofFormula (II) or pharmaceutically acceptable salts thereof wherein:

X is CH;

R¹ is (C₁-C₄)alkoxy;

each R² is independently halogen;

R⁷ is hydrogen or halogen;

R⁸ is hydrogen, fluorine, chlorine, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,cyano, (C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy-,(C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, or —CONH₂; wherein said(C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-;

R⁹ is halo(C₁-C₄)alkyl; and

n is 1 or 2.

In a particular embodiment, this invention relates to compounds ofFormula (II) or pharmaceutically acceptable salts thereof wherein:

X is N;

R¹ is (C₁-C₄)alkoxy;

each R² is independently halogen;

R⁷ is hydrogen or halogen;

R⁸ is hydrogen, fluorine, chlorine, (C₁-C₆)alkyl, halo(C₁-C₄)alkyl,cyano, (C₁-C₄)alkoxy, hydroxy(C₂-C₄)alkoxy-,(C₁-C₄)alkoxy(C₂-C₄)alkoxy-, amino(C₂-C₄)alkoxy-,((C₁-C₄/alkyl)amino(C₂-C₄)alkoxy-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino(C₂-C₄)alkoxy-, or —CONH₂; wherein said(C₁-C₆)alkyl is optionally substituted by cyano, hydroxyl,(C₁-C₄)alkoxy, amino, ((C₁-C₄)alkyl)amino-, or((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-;

R⁹ is halo(C₁-C₄)alkyl; and

n is 1 or 2.

This invention also relates to compounds that are exemplified in theExperimental section.

Specific compounds of this invention include:

-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide;-   N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide;-   N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,6-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide;-   N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide;-   N-(6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)ace    tamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide;-   N-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(6-(1-cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)ace    tamide;-   N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide;-   N-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   4-(2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)benzamide;-   N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(3,5-bis    (trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide;-   N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamide;-   N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide;-   2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide;-   N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;-   2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide;    and-   N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;    -   or pharmaceutically acceptable salts thereof.

A person of ordinary skills in the art recognizes that compounds of thepresent invention may have alternative names when different namingsoftware is used.

This invention also relates to compounds of Formula (I) or (II) or anyof the exemplified compounds, or their pharmaceutically acceptable saltsthereof, for use in therapy. In particular, for use in the treatment ofdiseases mediated by RET: irritable bowel syndrome (IBS) includingdiarrhea-predominant, constipation-predominant or alternating stoolpattern, functional bloating, functional constipation, functionaldiarrhea, unspecified functional bowel disorder, functional abdominalpain syndrome, chronic idiopathic constipation, functional esophagealdisorders, functional gastroduodenal disorders, functional anorectalpain, inflammatory bowel disease, proliferative diseases such asnon-small cell lung cancer, hepatocellular carcinoma, colorectal cancer,medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroidcancer, papillary thyroid cancer, brain tumors, peritoneal cavitycancer, solid tumors, other lung cancer, head and neck cancer, gliomas,neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breastcancer, fallopian tube cancer, ovarian cancer, transitional cell cancer,prostate cancer, caner of the esophagus and gastroesophageal junction,biliary cancer and adenocarcinoma. In particular, this invention relatesto compounds of Formula (I) or (II) or any of the exemplified compounds,or their pharmaceutically acceptable salts thereof, for use in thetreatment of irritable bowel syndrome (IBS) includingdiarrhea-predominant, constipation-predominant or alternating stoolpattern, functional bloating, functional constipation, functionaldiarrhea, unspecified functional bowel disorder, functional abdominalpain syndrome, chronic idiopathic constipation, functional esophagealdisorders, functional gastroduodenal disorders, functional anorectalpain, inflammatory bowel disease, non-small cell lung cancer,hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer,follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroidcancer, brain tumors, peritoneal cavity cancer, solid tumors, other lungcancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-LindauSyndrome and kidney tumors, breast cancer, fallopian tube cancer,ovarian cancer, transitional cell cancer, prostate cancer, cancer of theesophagus and gastroesophageal junction, biliary cancer andadenocarcinoma.

This invention also relates to compounds of Formula (I) or (II) or anyof the exemplified compounds, or their pharmaceutically acceptable saltsthereof, for use as a medicament. In another embodiment, the inventionrelates to the use of compounds of the invention in the preparation of amedicament for the treatment of diseases mediated by RET. This inventionalso relates to compounds of Formula (I) or (II) or any of theexemplified compounds, or their pharmaceutically acceptable saltsthereof, in the manufacture of a medicament for the treatment ofirritable bowel syndrome. This invention also relates to compounds ofFormula (I) or (II) or any of the exemplified compounds, or theirpharmaceutically acceptable salts thereof, in the manufacture of amedicament for the treatment of cancer.

This invention also relates to the use of compounds of Formula (I) or(II) or any of the exemplified compounds in therapy. The inventionfurther includes the use of compounds of the invention as an activetherapeutic substance, in particular in the treatment of diseasesmediated by RET. This invention also relates to the use of compounds ofFormula (I) or (II) or any of the exemplified compounds for thetreatment of irritable bowel syndrome. This invention also relates tothe use of compounds of Formula (I) or (II) or any of the exemplifiedcompounds for the treatment of cancer.

Because of their potential use in medicine, the salts of the compoundsof Formula (I) are preferably pharmaceutically acceptable. Suitablepharmaceutically acceptable salts include those described by Berge,Bighley, and Monkhouse, J. Pharm. Sci. (1977) 66, pp 1-19. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention. Salts of thedisclosed compounds containing a basic amine or other basic functionalgroup may be prepared by any suitable method known in the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like, or with an organic acid, such as acetic acid, trifluoroaceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,pyranosidyl acid, such as glucuronic acid or galacturonic acid,alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid,such as aspartic acid or glutamic acid, aromatic acid, such as benzoicacid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid or the like. Examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides,iodides, acetates, propionates, decanoates, caprylates, acrylates,formates, isobutyrates, caproates, heptanoates, propiolates, oxalates,malonates succinates, suberates, sebacates, fumarates, maleates,butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates,lactates, γ-hydroxybutyrates, glycolates, tartrates mandelates, andsulfonates, such as xylenesulfonates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates andnaphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or otheracidic functional group can be prepared by reacting with a suitablebase. Such a pharmaceutically acceptable salt may be made with a basewhich affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, choline, quinine, quinoline,and basic amino acid such as lysine and arginine.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of this invention and these should beconsidered to form a further aspect of the invention. These salts, suchas trifluoroacetate, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts.

If a compound of the invention containing a basic amine or other basicfunctional group is isolated as a salt, the corresponding free base formof that compound may be prepared by any suitable method known to theart, including treatment of the salt with an inorganic or organic base,suitably an inorganic or organic base having a higher pK_(a) than thefree base form of the compound. Similarly, if a compound of theinvention containing a carboxylic acid or other acidic functional groupis isolated as a salt, the corresponding free acid form of that compoundmay be prepared by any suitable method known to the art, includingtreatment of the salt with an inorganic or organic acid, suitably aninorganic or organic acid having a lower pK_(a) than the free acid formof the compound.

As used herein, the term “a compound of Formula (I)” or “the compound ofFormula (I)” refers to one or more compounds according to Formula (I).The compound of Formula (I) may exist in solid or liquid form. In thesolid state, it may exist in crystalline or noncrystalline form, or as amixture thereof. The skilled artisan will appreciate thatpharmaceutically acceptable solvates may be formed for crystalline ornon-crystalline compounds. In crystalline solvates, solvent moleculesare incorporated into the crystalline lattice during crystallization.Solvates may involve non-aqueous solvents such as, but not limited to,ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate,or they may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent incorporatedinto the crystalline lattice are typically referred to as “hydrates.”Hydrates include stoichiometric hydrates as well as compositionscontaining variable amounts of water. The invention includes all suchsolvates.

The skilled artisan will further appreciate that certain compounds ofthe invention that exist in crystalline form, including the varioussolvates thereof, may exhibit polymorphism (i.e. the capacity to occurin different crystalline structures). These different crystalline formsare typically known as “polymorphs.” The invention includes all suchpolymorphs. Polymorphs have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. The skilled artisan willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The compound of Formula (I) or (II) or salts thereof may exist instereoisomeric forms (e.g., it contains one or more asymmetric carbonatoms). The individual stereoisomers (enantiomers and diastereomers) andmixtures of these are included within the scope of the presentinvention. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures.

Likewise, it is understood that a compound or salt of Formula (I) or(II) may exist in tautomeric forms other than that shown in the formulaand these are also included within the scope of the present invention.For example, while the compounds of Formula (I) and (II) are depicted ascontaining a pyridin-2-one moiety, the corresponding 2-hydroxypyridinetautomer is also included within the scope of the present invention. Itis to be understood that the present invention includes all combinationsand subsets of the particular groups defined hereinabove.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of Formula (I) or (II), which may bemade prior to or following a final deprotection stage, may not possesspharmacological activity as such, but may, in certain instances, beadministered orally or parenterally and thereafter metabolized in thebody to form compounds of the invention which are pharmacologicallyactive. Such derivatives may therefore be described as “prodrugs”.Further, certain compounds of the invention may act as prodrugs of othercompounds of the invention. All protected derivatives and prodrugs ofcompounds of the invention are included within the scope of theinvention.

Examples of suitable pro-drugs for the compounds of the presentinvention are described in Drugs of Today, Volume 19, Number 9, 1983, pp499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in“Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1.

It will further be appreciated by those skilled in the art, that certainmoieties, known to those skilled in the art as “pro-moieties”, forexample as described by H. Bundgaard in “Design of Prodrugs” may beplaced on appropriate functionalities when such functionalities arepresent within compounds of the invention. Preferred “pro-moieties” forcompounds of the invention include: ester, carbonate ester, hemi-ester,phosphate ester, nitro ester, sulfate ester, sulfoxide, amide,carbamate, azo-, phosphamide, glycoside, ether, acetal, and ketalderivatives of the compounds of Formula (I) or (II).

Administration of a compound of the invention as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the compound in vivo; (b) modify the duration of action of thecompound in vivo; (c) modify the transportation or distribution of thecompound in vivo; (d) modify the solubility of the compound in vivo; and(e) overcome or overcome a side effect or other difficulty encounteredwith the compound.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., isotopes areparticularly preferred for their ease of preparation and detectability.¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiontomography), and ¹²⁵1 isotopes are particularly useful in SPECT (singlephoton emission computerized tomography), all useful in brain imaging.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula (I) and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

DEFINITIONS

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein, the term “alkyl” represents a saturated, straight, orbranched hydrocarbon moiety. The term “(C₁-C₆)alkyl” refers to an alkylmoiety containing from 1 to 6 carbon atoms. Exemplary alkyls include,but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, s-butyl, t-butyl, pentyl, and hexyl.

When the term “alkyl” is used in combination with other substituentgroups, such as “halo(C₁-C₄)alkyl” or “hydroxy(C₁-C₄)alkyl”, the term“alkyl” is intended to encompass a divalent straight or branched-chainhydrocarbon radical, wherein the point of attachment is through thealkyl moiety. The term “halo(C₁-C₄)alkyl” is intended to mean a radicalhaving one or more halogen atoms, which may be the same or different, atone or more carbon atoms of an alkyl moiety containing from 1 to 4carbon atoms, which is a straight or branched-chain carbon radical.Examples of “halo(C₁-C₄)alkyl” groups useful in the present inventioninclude, but are not limited to, —CF₃ (trifluoromethyl), —CCl₃(trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, andhexafluoroisopropyl. Examples of “hydroxy(C₁-C₄)alkyl” groups useful inthe present invention include, but are not limited to, hydroxymethyl,hydroxyethyl, and hydroxyisopropyl.

“Alkoxy” refers to a group containing an alkyl radical, definedhereinabove, attached through an oxygen linking atom. The term“(C₁-C₄)alkoxy” refers to a straight- or branched-chain hydrocarbonradical having at least 1 and up to 4 carbon atoms attached through anoxygen linking atom. Exemplary “(C₁-C₄)alkoxy” groups useful in thepresent invention include, but are not limited to, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

When the term “alkoxy” is used in combination with other substituentgroups, such as “halo(C₁-C₆)alkoxy”, “hydroxy(C₂-C₄)alkoxy”, or“(C₁-C₄)alkoxy(C₂-C₄)alkoxy”, the term “alkoxy” is intended to encompassa divalent straight or branched-chain hydrocarbon radical, wherein thepoint of attachment is to the alkyl moiety through an oxygen linkingatom. The term “halo(C₁-C₆)alkoxy” refers to a straight- orbranched-chain hydrocarbon radical, having at least 1 and up to 6 carbonatoms with one or more halogen atoms, which may be the same ordifferent, attached to one or more carbon atoms, which radical isattached through an oxygen linking atom. Exemplary “halo(C₁-C₆)alkoxy”groups useful in the present invention include, but are not limited to,—OCHF₂ (difluoromethoxy), —OCF₃ (trifluoromethoxy), and —OCH(CF₃)₂(hexafluoroisopropoxy). Examples of “hydroxy(C₂-C₄)alkoxy” groups usefulin the present invention include, but are not limited to,2-hydroxyethoxy and 2-hydroxyisopropoxy. Examples of“(C₁-C₄)alkoxy(C₂-C₄)alkoxy” groups useful in the present inventioninclude, but are not limited to, 2-methoxyethoxy, 2-ethoxyethoxy,2-isopropoxyethoxy, 2-methoxyisopropoxy, and 2-ethoxyisopropoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatic,saturated, cyclic hydrocarbon ring containing the specified number ofcarbon atoms. The term “(C₃-C₆)cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to six ring carbon atoms.Exemplary “(C₃-C₆)cycloalkyl” groups useful in the present inventioninclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “cycloalkyloxy-” refers to a group containing acycloalkyl radical, defined hereinabove, attached through an oxygenlinking atom. Exemplary “(C₃-C₈)cycloalkyloxy-” groups useful in thepresent invention include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

As used herein, “4- to 6-membered heterocycloalkyl” represents a groupor moiety comprising a non aromatic, monovalent monocyclic radical,which is saturated or partially unsaturated, containing 4, 5, or 6 ringatoms, which includes one or two heteroatoms selected independently fromoxygen, sulfur, and nitrogen. Illustrative examples of 4- to 6-memberedheterocycloalkyl groups useful in the present invention include, but arenot limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl,pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl,tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, and1,4-dithianyl

As used herein, “5- or 6-membered heteroaryl” represents a group ormoiety comprising an aromatic monovalent monocyclic radical, containing5 or 6 ring atoms, including at least one carbon atom and 1 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur.Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, orsulfur ring heteroatom, and optionally contain 1, 2, or 3 additionalnitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2,or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or6-membered heteroaryl groups useful in the present invention include,but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, and triazinyl.

The terms “halogen” and “halo” represent chloro, fluoro, bromo, or iodosubstituents. “Hydroxy” or “hydroxyl” is intended to mean the radical—OH. As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “optionally substituted” indicates that agroup, such as alkyl, cycloalkyl, phenyl, or heteroaryl, may beunsubstituted, or the group may be substituted with one or moresubstituent(s) as defined. In the case where groups may be selected froma number of alternative groups the selected groups may be the same ordifferent.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different. The alternative definitions for the variousgroups and substituent groups of Formula (I) or (II) provided throughoutthe specification are intended to particularly describe each compoundspecies disclosed herein, individually, as well as groups of one or morecompound species. The scope of this invention includes any combinationof these group and substituent group definitions.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the desired biological activity of the subjectcompound and exhibit minimal undesired toxicological effects. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

Pharmaceutical Compositions

The invention further provides a pharmaceutical composition (alsoreferred to as pharmaceutical formulation) comprising a compound ofFormula (I) or (II) or a pharmaceutically acceptable salt thereof, andone or more excipients (also referred to as carriers and/or diluents inthe pharmaceutical arts). The excipients are pharmaceutically acceptablein the sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof (i.e., thepatient).

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In accordance with another aspect of the invention there is provided aprocess for the preparation of a pharmaceutical composition comprisingmixing (or admixing) a compound of Formula (I) or (II) or apharmaceutically acceptable salt thereof, with at least one excipient.

Pharmaceutical compositions may be in unit dose form containing apredetermined amount of active ingredient per unit dose. Such a unit maycontain a therapeutically effective dose of the compound of Formula (I)or (II) or a pharmaceutically acceptable salt thereof, or a fraction ofa therapeutically effective dose such that multiple unit dosage formsmight be administered at a given time to achieve the desiredtherapeutically effective dose. Preferred unit dosage formulations arethose containing a daily dose or sub-dose, as herein above recited, oran appropriate fraction thereof, of an active ingredient. Furthermore,such pharmaceutical compositions may be prepared by any of the methodswell-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example, by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous, or intradermal) routes. Such compositionsmay be prepared by any method known in the art of pharmacy, for example,by bringing into association the active ingredient with theexcipient(s).

When adapted for oral administration, pharmaceutical compositions may bein discrete units such as tablets or capsules, powders or granules,solutions or suspensions in aqueous or non-aqueous liquids, edible foamsor whips, oil-in-water liquid emulsions or water-in-oil liquidemulsions. The compound or salt thereof of the invention or thepharmaceutical composition of the invention may also be incorporatedinto a candy, a wafer, and/or tongue tape formulation for administrationas a “quick-dissolve” medicine.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders or granules are prepared bycomminuting the compound to a suitable fine size and mixing with asimilarly comminuted pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin or non-gelatinous sheaths. Glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate, solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate, or sodium carbonate can also beadded to improve the availability of the medicine when the capsule isingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugars,such as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, andaliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt, and/oran absorption agent such as bentonite, kaolin, or dicalcium phosphate.The powder mixture can be granulated by wetting a binder such as asyrup, starch paste, acadia mucilage, or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through a tablet machine,resulting in imperfectly formed slugs broken into granules. The granulescan be lubricated to prevent sticking to the tablet forming dies bymeans of the addition of stearic acid, a stearate salt, talc, or mineraloil. The lubricated mixture is then compressed into tablets. Thecompound or salt of the present invention can also be combined with afree-flowing inert carrier and compressed into tablets directly withoutgoing through the granulating or slugging steps. A clear opaqueprotective coating consisting of a sealing coat of shellac, a coating ofsugar, or polymeric material, and a polish coating of wax can beprovided. Dyestuffs can be added to these coatings to distinguishdifferent dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of active ingredient. Syrups can be prepared by dissolving thecompound or salt thereof of the invention in a suitably flavouredaqueous solution, while elixirs are prepared through the use of anon-toxic alcoholic vehicle. Suspensions can be formulated by dispersingthe compound or salt of the invention in a non-toxic vehicle.Solubilizers and emulsifiers, such as ethoxylated isostearyl alcoholsand polyoxyethylene sorbitol ethers, preservatives, flavor additivessuch as peppermint oil, natural sweeteners, saccharin, or otherartificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred fordelivery of the pharmaceutical composition.

As used herein, the term “treatment” refers to alleviating the specifiedcondition, eliminating or reducing one or more symptoms of thecondition, slowing or eliminating the progression of the condition, andpreventing or delaying the reoccurrence of the condition in a previouslyafflicted or diagnosed patient or subject.

The present invention provides a method of treatment in a mammal,especially a human, suffering from irritable bowel syndrome (IBS)including diarrhea-predominant, constipation-predominant or alternatingstool pattern, functional bloating, functional constipation, functionaldiarrhea, unspecified functional bowel disorder, functional abdominalpain syndrome, chronic idiopathic constipation, functional esophagealdisorders, functional gastroduodenal disorders, functional anorectalpain, inflammatory bowel disease, proliferative diseases such asnon-small cell lung cancer, hepatocellular carcinoma, colorectal cancer,medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroidcancer, papillary thyroid cancer, brain tumors, peritoneal cavitycancer, solid tumors, other lung cancer, head and neck cancer, gliomas,neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breastcancer, fallopian tube cancer, ovarian cancer, transitional cell cancer,prostate cancer, caner of the esophagus and gastroesophageal junction,biliary cancer and adenocarcinoma or a combination thereof. Suchtreatment comprises the step of administering a therapeuticallyeffective amount of a compound of Formula (I) or (II) or apharmaceutically acceptable salt thereof, to said mammal, particularly ahuman. Treatment can also comprise the step of administering atherapeutically effective amount of a pharmaceutical compositioncontaining a compound of Formula (I) or (II) or a pharmaceuticallyacceptable salt thereof, to said mammal, particularly a human.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function. Foruse in therapy, therapeutically effective amounts of a compound ofFormula (I) or (II), as well as salts thereof, may be administered asthe raw chemical. Additionally, the active ingredient may be presentedas a pharmaceutical composition. While it is possible that, for use intherapy, a therapeutically effective amount of a compound of Formula (I)or (II) or a pharmaceutically acceptable salt thereof, may beadministered as the raw chemical, it is typically presented as theactive ingredient of a pharmaceutical composition or formulation.

The precise therapeutically effective amount of a compound or saltthereof of the invention will depend on a number of factors, including,but not limited to, the age and weight of the subject (patient) beingtreated, the precise disorder requiring treatment and its severity, thenature of the pharmaceutical formulation/composition, and route ofadministration, and will ultimately be at the discretion of theattending physician or veterinarian. Typically, a compound of Formula(I) or (II) or a pharmaceutically acceptable salt thereof, will be givenfor the treatment in the range of about 0.1 to 100 mg/kg body weight ofrecipient (patient, mammal) per day and more usually in the range of 0.1to 10 mg/kg body weight per day. Acceptable daily dosages may be fromabout 0.1 to about 1000 mg/day, and preferably from about 1 to about 100mg/day. This amount may be given in a single dose per day or in a number(such as two, three, four, five, or more) of sub-doses per day such thatthe total daily dose is the same. An effective amount of a salt thereofmay be determined as a proportion of the effective amount of thecompound of Formula (I) or (II) per se. Similar dosages should beappropriate for treatment of the other conditions referred herein fortreatment. In general, determination of appropriate dosing can bereadily arrived at by one skilled in medicine or the pharmacy art.

The compounds of the invention may be used alone or in combination withone or more other therapeutic agents. Accordingly the present inventionprovides a combination comprising a compound of Formula (I) or apharmaceutically acceptable salt thereof and one or more othertherapeutic agents. Such combinations may be presented individually(wherein each active is in separate composition) or the actives arepresented in a combined composition.

The instant compounds can be combined with or co-administered with othertherapeutic agents, particularly agents that may enhance the activity ortime of disposition of the compounds. Combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and the use of at least one other treatment method. In oneembodiment, combination therapies according to the invention comprisethe administration of at least one compound of the invention andsurgical therapy. In one embodiment, combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and radiotherapy. In one embodiment, combination therapiesaccording to the invention comprise the administration of at least onecompound of the invention and at least one supportive care agent (e.g.,at least one anti-emetic agent). In one embodiment, combinationtherapies according to the present invention comprise the administrationof at least one compound of the invention and at least one otherchemotherapeutic agent. In one particular embodiment, the inventioncomprises the administration of at least one compound of the inventionand at least one anti-neoplastic agent. In yet another embodiment, theinvention comprises a therapeutic regimen where the RET inhibitors ofthis disclosure are not in and of themselves active or significantlyactive, but when combined with another therapy, which may or may not beactive as a standalone therapy, the combination provides a usefultherapeutic outcome.

By the term “co-administering” and derivatives thereof as used hereinrefers to either simultaneous administration or any manner of separatesequential administration of a RET inhibiting compound, as describedherein, and a further active ingredient or ingredients, particularlythose known to be useful in the treatment of cancer, includingchemotherapy and radiation treatment. The term further active ingredientor ingredients, as used herein, includes any compound or therapeuticagent known to or that demonstrates advantageous properties whenadministered to a patient in need of treatment for cancer. Preferably,if the administration is not simultaneous, the compounds areadministered in a close time proximity to each other. Furthermore, itdoes not matter if the compounds are administered in the same dosageform, e.g. one compound may be administered topically and anothercompound may be administered orally. Typically, any anti-neoplasticagent that has activity versus a susceptible tumor being treated may beco-administered in the treatment of specified cancers in the presentinvention. Examples of such agents can be found in Cancer Principles andPractice of Oncology by V. T. Devita and S. Hellman (editors), 6^(th)edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. Aperson of ordinary skill in the art would be able to discern whichcombinations of agents would be useful based on the particularcharacteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; DNA methyltransferase inhibitors such asazacitidine and decitabine; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; and cell cycle signaling inhibitors.

Typically, any chemotherapeutic agent that has activity against asusceptible neoplasm being treated may be utilized in combination withthe compounds the invention, provided that the particular agent isclinically compatible with therapy employing a compound of theinvention. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to: alkylating agents,anti-metabolites, antitumor antibiotics, antimitotic agents, nucleosideanalogues, topoisomerase I and II inhibitors, hormones and hormonalanalogues; retinoids, histone deacetylase inhibitors; signaltransduction pathway inhibitors including inhibitors of cell growth orgrowth factor function, angiogenesis inhibitors, and serine/threonine orother kinase inhibitors; cyclin dependent kinase inhibitors; antisensetherapies and immunotherapeutic agents, including monoclonals, vaccinesor other biological agents.

Nucleoside analogues are those compounds which are converted todeoxynucleotide triphosphates and incorporated into replicating DNA inplace of cytosine. DNA methyltransferases become covalently bound to themodified bases resulting in an inactive enzyme and reduced DNAmethylation. Examples of nucleoside analogues include azacitidine anddecitabine which are used for the treatment of myelodysplastic disorder.Histone deacetylase (HDAC) inhibitors include vorinostat, for thetreatment of cutaneous T-cell lymphoma. HDACs modify chromatin throughthe deacetylation of histones. In addition, they have a variety ofsubstrates including numerous transcription factors and signalingmolecules. Other HDAC inhibitors are in development.

Signal transduction pathway inhibitors are those inhibitors which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation orsurvival. Signal transduction pathway inhibitors useful in the presentinvention include, but are not limited to, inhibitors of receptortyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domainblockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases,myoinositol signaling, and Ras oncogenes. Signal transduction pathwayinhibitors may be employed in combination with the compounds of theinvention in the compositions and methods described above.

Receptor kinase angiogenesis inhibitors may also find use in the presentinvention. Inhibitors of angiogenesis related to VEGFR and TIE-2 arediscussed above in regard to signal transduction inhibitors (both arereceptor tyrosine kinases). Other inhibitors may be used in combinationwith the compounds of the invention. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alpha beta₃) thatinhibit angiogenesis; endostatin and angiostatin (non-RTK) may alsoprove useful in combination with the compounds of the invention. Oneexample of a VEGFR antibody is bevacizumab (AVASTIN®).

Several inhibitors of growth factor receptors are under development andinclude ligand antagonists, antibodies, tyrosine kinase inhibitors,anti-sense oligonucleotides and aptamers. Any of these growth factorreceptor inhibitors may be employed in combination with the compounds ofthe invention in any of the compositions and methods/uses describedherein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibodyinhibitor of growth factor function. One example of an anti-erbB 1antibody inhibitor of growth factor function is cetuximab (Erbitux™,C225). Bevacizumab (Avastin®) is an example of a monoclonal antibodydirected against VEGFR. Examples of small molecule inhibitors ofepidermal growth factor receptors include but are not limited tolapatinib (Tykerb®) and erlotinib (TARCEVA®). Imatinib mesylate(GLEEVEC®) is one example of a PDGFR inhibitor. Examples of VEGFRinhibitors include pazopanib (Votrient®), ZD6474, AZD2171, PTK787,sunitinib and sorafenib.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate β-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem, Soc., 93:2325 (1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Int.Med., 111:273,1989) and for the treatment of breast cancer (Holmes etal., J. Nat. Cancer Inst., 83:1797,1991.). It is a potential candidatefor treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc.Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al.,Sem. Oncol., 20:56, 1990). The compound also shows potential for thetreatment of polycystic kidney disease (Woo et. al., Nature, 368:750.1994), lung cancer and malaria. Treatment of patients with paclitaxelresults in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide., 1998) related to theduration of dosing above a threshold concentration (50 nM) (Kearns, C.M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine N-tert-butyl ester,β-ester with 5β-20-epoxy-1,2α,4,7β, 10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate (NAVELBINC),is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a singleagent or in combination with other chemotherapeutic agents, such ascisplatin, in the treatment of various solid tumors, particularlynon-small cell lung, advanced breast, and hormone refractory prostatecancers. Myelosuppression is the most common dose limiting side effectof vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo aquation and form intra- and interstrand crosslinkswith DNA causing adverse biological effects to the tumor. Examples ofplatinum coordination complexes include, but are not limited to,cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2+0,0′],is commercially available as PARAPLATIN® as an injectable solution.Carboplatin is primarily indicated in the first and second linetreatment of advanced ovarian carcinoma. Bone marrow suppression is thedose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,24bis(2-chloroethypaminoltetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 44bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan. Carmustine,1,34bis(2-chloroethyl)-1-nitrosourea, is commercially available assingle vials of lyophilized material as BiCNU®. Carmustine is indicatedfor the palliative treatment as a single agent or in combination withother agents for brain tumors, multiple myeloma, Hodgkin's disease, andnon-Hodgkin's lymphomas. Delayed myelosuppression is the most commondose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also known as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)-oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin, (8 S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as aninjectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarilyindicated for the treatment of acute lymphoblastic leukemia and acutemyeloblastic leukemia, but is also a useful component in the treatmentof some solid tumors and lymphomas. Myelosuppression is the most commondose limiting side effect of doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranosidel, is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leukopenialeukopenia tends to bemore severe than thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-[3-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leukopenialeukopenia andthrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leukopenialeukopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.

Myelosuppression, including leukopenialeukopenia, thrombocytopenia, andanemia, is the most common dose limiting side effect of thioguanineadministration. However, gastrointestinal side effects occur and can bedose limiting. Other purine analogs include pentostatin,erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride((3-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leukopenialeukopenia, thrombocytopenia, andanemia, is the most common dose limiting side effect of gemcitabineadministration.

Methotrexate,N-[4[[2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.Myelosuppression (leukopenia, thrombocytopenia, and anemia) andmucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl,(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commerciallyavailable as the injectable solution HYCAMTIN®. Topotecan is aderivative of camptothecin which binds to the topoisomerase I—DNAcomplex and prevents religation of singles strand breaks caused byTopoisomerase I in response to torsional strain of the DNA molecule.Topotecan is indicated for second line treatment of metastatic carcinomaof the ovary and small cell lung cancer. The dose limiting side effectof topotecan HCl is myelosuppression, primarily neutropenia.

Compounds Preparation Generic Synthesis Schemes

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working examples. The skilled artisan willappreciate that if a substituent described herein is not compatible withthe synthetic methods described herein, the substituent may be protectedwith a suitable protecting group that is stable to the reactionconditions. The protecting group may be removed at a suitable point inthe reaction sequence to provide a desired intermediate or targetcompound. In all of the schemes described below, protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts, (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of the present invention.

The synthesis of the compounds of the general Formula (I) andpharmaceutically acceptable derivatives and salts thereof may beaccomplished as outlined below in Schemes 1-5 by those skilled in theart. In the following description, the groups are as defined above forcompounds of Formula (I) unless otherwise indicated. Starting materialsare commercially available or are made from commercially availablestarting materials using methods known to those skilled in the art.

Compounds of Formula (I) may be prepared as illustrated in Scheme 1.Appropriately substituted acid A may be coupled with a primary amineunder amide bond formation conditions, such as HOBt, EDC, and Et₃N inDMF, to yield aryl bromide intermediate B. Intermediate B can be coupledwith boronate ester intermediate C under palladium coupling conditions,such as with PdCl₂(dppf) and Cs₂CO₃, to yield intermediate D.Deprotection of the paramethoxybenzyl (PMB) or benzyl (Bn) moiety canaccomplished in the presence of palladium on carbon under a H₂atmosphere resulting in compounds of Formula (I).

Intermediate D may also be prepared as illustrated in Scheme 2. Arylbromide B can be converted to the boronate ester under appropriateconditions, such as with PdCl₂(dppf) and KOAc in 1,4-dioxane, to yieldboronate ester intermediate E. An appropriately substituted3-bromopyridine can then be coupled to intermediate E under palladiumcoupling conditions, such as with PdCl₂(dppf) and Cs₂CO₃, to yieldintermediate D. Conditions similar to those in scheme 1 can furthertransform intermediate D to compounds of Formula (I).

Intermediate D may also be prepared as illustrated in Scheme 3. Arylbromide F can be converted to the boronate ester under appropriateconditions, such as with PdCl₂(dppf) and KOAc in 1,4-dioxane, to yieldboronate ester intermediate G. Methyl ester intermediate G can beconverted to the primary amide intermediate H under basic conditionswith ammonia. An appropriately substituted 3-bromopyridine can then becoupled to intermediate H under palladium coupling conditions, such aswith PdCl₂(dppf) and Cs₂CO₃, to yield intermediate I. Intermediate I canbe further transformed into intermediate D by coupling with anappropriately substituted aryl bromide under appropriate conditions,such as with Pd₂(dba)₃, Xantphos, and Cs₂CO₃ in 1,4-dioxane. Conditionssimilar to those in scheme 1 can further transform intermediate D tocompounds of Formula (I).

Intermediate I may also be prepared as illustrated in Scheme 4. Arylbromide intermediate J can be coupled to a substituted pyridine boronateester under palladium coupling conditions, such as with PdCl₂(dppf) andCs₂CO₃, to yield intermediate I. Intermediate I can be furthertransformed to compounds of Formula (I) as demonstrated in Schemes 3 and1.

Compounds of Formula (I) may also be prepared as illustrated in Scheme5. Appropriately substituted acid A may be coupled to an appropriatelysubstituted pyridin-3-yl boronate ester under palladium couplingconditions, such as with PdCl₂(dppf) and Cs₂CO₃, to yield intermediateK. Deprotection of the paramethoxybenzyl (PMB) or benzyl (Bn) moiety ofintermediate K in the presence of palladium on carbon in a H₂ atmosphereyields intermediate L. Acid intermediate L can then be coupled to anappropriately substituted primary amine under amide bond formationconditions, such as HOBt, EDC, and Et₃N in DMF, to yield compounds offormula (I).

Experimentals

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention. Unless otherwise noted, reagents are commercially availableor are prepared according to procedures in the literature. The symbolsand conventions used in the descriptions of processes, schemes, andexamples are consistent with those used in the contemporary scientificliterature, for example, the Journal of the American Chemical Society orthe Journal of Biological Chemistry.

In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Couplingconstants (J) are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), dd (double doublet), dt (double triplet), dq(double quartet), m (multiplet), br (broad).

Flash column chromatography was performed on silica gel.

The naming programs used are ACDLABs 11.0 Namebatch, ACD IUPAC, orChemDraw®.

ABBREVIATIONS

BH₃.DMS borane dimethyl sulfide complexBoc₂O di-tent-butyl dicarbonateCDCl₃ chloroform-dCD₃OD methanol-d₄CHCl₃ chloroformCs₂CO₃ cesium carbonateDCE dichloroethaneDCM dichloromethaneDIBAL-H diisobutylaluminum hydrideDIEA diisopropyle thylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxideEA ethyl acetateEDC N-(3-dimethylaminopropyl)-N′-ethylcarbonateES-LCMS electrospray liquid chromatography-mass spectrometryEt₃N triethylamineEtOH ethanolg gram(s)h hour(s)H₂ hydrogen gasHATU 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHCl hydrochloric acidH₂O waterHOBt hydroxybenzotriazoleHPLC high performance liquid chromatographyH₂SO₄ sulfuric acidin vacuo under vacuumK₂CO₃ potassium carbonateKCN potassium cyanideKOAc potassium acetateKOH potassium hydroxideLAH lithium aluminium hydrideLCMS liquid chromatography-mass spectrometryLiOH.H₂O lithium hydroxide hydratem-CPBA meta-chloroperoxybenzoic acidMeCN acetonitrileMeI methyl iodideMeOH methanolmg milligram(s)MgSO₄ magnesium sulfatemin minute(s)mL milliliter(s)mmol millimole(s)N₂ nitrogen gasNaBH₄ sodium borohydrideNaCN sodium cyanideNa₂CO₃ sodium carbonateNaH sodium hydrideNaHCO₃ sodium bicarbonateNaOH sodium hydroxideNa₂SO₄ sodium sulfateNa₂S₂O₃ sodium thiosulfate

NBS N-bromosuccinimide

n-BuLi n-butyl lithiumNH₄Cl ammonium chlorideNH₄OH ammonium hydroxide

NIS N-iodosuccinimide

NMR nuclear magnetic resonancePBr₃ phosphorus tribromidePd/C palladium on carbonPdCl₂(dppf) 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)PE petroleum etherPMB p-methoxybenzylPOCl₃ phosphorus oxychloridert room temperatureSOCl₂ thionyl chlorideTBME tert-butyl methyl etherTBS tert-butyldimethylsilylTBSCl tert-butyldimethylsilyl chlorideTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromotrographyT₃P® propylphosphonic anhydrideXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

PREPARATION OF INTERMEDIATES Intermediate 1:3-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Step 1: 3-Bromo-5-ethoxypyridine

A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K₂CO₃ (111 g, 805mmol) and iodoethane (69.0 g, 443 mmol) in DMF (700 mL) was stirred for16 h at 25° C. Then the mixture was concentrated to give the residuewhich was extracted with DCM (2×200 mL), dried over Na₂SO₄, filtered,and concentrated to give 3-bromo-5-ethoxypyridine (53 g, 218 mmol, 54.2%yield): NMR (400 MHz, CD₃OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H),4.13-4.07 (m, 2H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 202 (M+H).

Step 2: 3-Bromo-5-ethoxypyridine 1-oxide

To a solution of 3-bromo-5-ethoxypyridine (53 g, 262 mmol) in DCM (200mL) at 0° C. was slowly added m-CPBA (67.9 g, 393 mmol) over 30 min.After the resulting solution was stirred for 15 h, the mixture waswashed with NaS₂O₃ solution and extracted with DCM (2×300 mL), driedover Na₂SO₄, filtered, and the organic phase was concentrated to give3-bromo-5-ethoxypyridine 1-oxide (40 g, 165 mmol, 62.9% yield): ¹H NMR(400 MHz, CD₃OD) δ 8.19-8.18 (m, 1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m,1H), 4.17-4.15 (d, J=8.8 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); ES-LCMS m/z217 (M+H).

Step 3: 5-Bromo-2-chloro-3-ethoxypyridine

To a solution of 3-bromo-5-ethoxypyridine 1-oxide (40 g, 183 mmol) inDCM (200 mL) at 0° C. was slowly added POCl₃ (159 mL, 1701 mmol) over 30min. Then the resulting solution was warmed to 45° C. for 15 h. Themixture was concentrated and extracted with DCM (2×200 mL), dried overNa₂SO₄, filtered, and concentrated to give5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9 mmol, 33.2% yield): ¹H NMR(400 MHz, CD₃OD) δ 8.00-7.99 (d, J=2.0 Hz, 1H), 7.65-7.64 (d, J=2.0 Hz,1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).

Step 4: 5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF(200 mL) was added NaH (3.96 g, 165 mmol) at 0° C. After the mixture wasstirred for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g, 110 mmol)was added to above mixture; the mixture was stirred for 12 h at 80-90°C. The mixture was quenched by H₂O (20 mL), extracted with DCM (2×200mL), dried over Na₂SO₄, filtered, and concentrated to give the residuewhich was purified by column chromatography (10% EA/90% PE, 360 g silicacolumn). All fractions found to contain product by TLC (EA/PE=5:1,R_(f)=0.5) were combined and concentrated to yield a white solid of5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (36 g, 74.5 mmol,67.8% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.71 (d, J=2.0 Hz, 1H),7.36-7.31 (m, 3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H)3.77 (s, 3H), 2.37 (d, J=7.0 Hz, 3H); ES-LCMS m/z 338 (M+H).

Step 5:3-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (10g, 29.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.26 g,32.5 mmol) and KOAc (7.25 g, 73.9 mmol) in 1,4-dioxane (250 mL) stirredunder nitrogen at 20° C. was added PdCl₂(dppf) (1.082 g, 1.478 mmol) inone charge. The reaction mixture was stirred at 100° C. for 3 h. Themixture was filtered and the filtrate was concentrated in vacuo to givethe crude product. The crude material was purified by silica columnchromatography (PE/EA=10:1). All fractions found to contain product byTLC (PE/EA=10:1, R_(f)=0.6) were combined and concentrated to yield awhite solid of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(9.2 g, 23.88 mmol, 81.0% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s,1H), 7.42 (d, J=8.8 Hz, 2H), 7.33 (s, 1H), 6.88-6.85 (m, 2H), 5.45 (s,2H), 4.11-4.06 (m, 2H), 3.78 (s, 3H), 1.43 (t, J=7.0 Hz, 3H), 1.33 (s,12H); ES-LCMS m/z 386.0 (M+H).

Intermediate 2: 4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)aniline

Step 1: 1-(2-(Benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene

To a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91mmol) in DMF (50 mL) was added K₂CO₃ (6.61 g, 47.8 mmol) and2-(benzyloxy)ethanol (4.00 g, 26.3 mmol) at rt. The mixture was stirredat 110° C. for 12 h. LCMS and TLC (PE/EA=5:1, R_(f)=0.4) showed thereaction was finished. The mixture was filtrated, and the filtrate wasconcentrated to give crude product, which was purified by silica gelcolumn to obtain 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (7.1 g, 18.18 mmol, 76.0% yield): ¹H NMR (400 MHz, CDCl₃) 8.49(d, J=2.4 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 7.54-7.28 (m, 5H), 7.13 (d,J=8.4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J=4.8 Hz, 2H), 3.89 (t, J=3.6 Hz,2H); ES-LCMS m/z 342(M+H).

Step 2: 4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)aniline

To a mixture of1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (8.1 g, 23.73mmol) in MeOH (100 mL) was added zinc (15.52 g, 237 mmol) and NH₄Cl(12.70 g, 237 mmol). The mixture was stirred at 20° C. for 3 h. LCMSshowed the reaction was finished. The mixture was filtered, and thefiltrate was concentrated to give crude product, which was purified bysilica gel column (PE/EA=5:1, R_(f)=0.4) to obtain4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (5.1 g, 14.40 mmol,60.7% yield). ¹H NMR (400 MHz, CDCl₃) 7.35-7.24 (m, 5H), 6.81 (t, J=8.4Hz, 2H), 6.78 (d, J=2.8 Hz, 1H), 4.63 (s, 2H), 4.13 (t, J=4.8 Hz, 2H),3.83 (t, J=3.6 Hz, 2H); ES-LCMS m/z 312(M+H).

Intermediate 3:4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline

Step 1: Ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate

To a mixture of diisopropylamine (8.00 mL, 57.1 mmol) in THF (300 mL)cooled to 0° C. was added n-BuLi (24.60 mL, 61.5 mmol) dropwise. Themixture was stirred at 0° C. for 1 h. Then to the mixture cooled to −30°C. was added a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF(2 mL). The mixture was stirred at −30° C. for 1 h. To the mixture wasadded a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g,43.9 mmol) in THF (5 mL) at −30° C. The whole mixture was stirred at−30° C. for 3 h and then stirred at 25° C. for 12 h. The mixture wasquenched with aqueous NH₄Cl and extracted with EA. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by silica column chromatography(PE/EA=200:1). All fractions found to contain product by TLC(PE/EA=10:1, R_(f)=0.6) were combined and concentrated to yield a lightyellow solid of ethyl2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 35.3 mmol,80.0% yield): NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.0 Hz, 1H), 7.41 (t,J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.17 (q,J=7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s, 6H);ES-LCMS m/z 275 (M+H).

Step 2: Ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate

To a solution of ethyl2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 36.5 mmol)in H₂SO₄ (5 mL, 94 mmol) cooled to 0° C. was added potassiumnitroperoxous acid (4.05 g, 40.1 mmol) in portions. The mixture wasstirred at 0° C. for 30 min. The mixture was poured into ice-water andextracted with DCM. The organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated to give a yellow solid of ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g,24.54 mmol, 67.3% yield): ¹H NMR (400 MHz, CDCl₃) δ: 8.59 (d, J=2.4 Hz,1H), 8.47 (dd, J=2.4, 8.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 5.97-5.83 (m,2H); ES-LCMS m/z 320 (M+H).

Step 3: Ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

A reaction mixture of ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g,26.6 mmol) and Pd/C (0.283 g, 2.66 mmol) in MeOH (50 mL) washydrogenated using an H-cube (settings: 50° C., 50 psi, 24 h). Themixture was filtered and the filtrate was concentrated. The crudematerial was purified by silica column chromatography (PE/EA=10:1). Allfractions found to contain product by TLC (PE/EA=5:1, R_(f)=0.4) werecombined and concentrated to yield a off white solid of ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7 g, 22.42mmol, 84.0% yield): NMR (400 MHz, CDCl₃) δ: 6.98 (d, J=8.4 Hz, 1H), 6.91(d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 8.4 Hz, 1H), 4.15 (q, J=6.8 Hz, 2H),3.00 (s, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290(M+H).

Step 4: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

To a mixture of ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91mmol) in THF (200 mL) was added LAH (0.525 g, 13.83 mmol) in portions.The mixture was stirred at 25° C. for 10 h. The mixture was quenchedwith 15% aqueous NaOH (10 mL). The mixture was dried over Na₂SO₄. Themixture was filtered and the filtrate was concentrated. The residue waspurified by silica column chromatography (PE/EA=8:1). All fractionsfound to contain product by TLC (PE/EA=2:1, R_(f)=0.35) were combinedand concentrated to yield a light yellow oil of3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (1.1 g,4.45 mmol, 64.4% yield): ¹H NMR (400 MHz, MeOD) δ: 7.17 (d, J=8.4 Hz,1H), 6.98 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.4, 8.0 Hz, 1H), 3.31 (s, 2H),2.67 (d, J=1.2 Hz, 2H), 0.84 (s, 6H); ES-LCMS m/z 248 (M+H).

Step 5:4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline

To a mixture of3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg,1.213 mmol) in DCM (150 mL) was added imidazole (124 mg, 1.820 mmol) andTBSCl (219 mg, 1.456 mmol). Then the mixture was stirred at 25° C. for 5h. The mixture was filtered and the filtrate was concentrated. The crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.5) to yielda light yellow solid of4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline(350 mg, 0.930 mmol, 77.0% yield): ¹H NMR (400 MHz, CD₃C1) δ: 7.14 (d,J=8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.70 (dd, J=2.8, 8.4 Hz, 1H),3.20 (s, 2H), 2.62 (d, J=1.2 Hz, 2H), 0.87 (s, 9H), 0.73 (s, 6H), 0.00(s, 6H); ES-LCMS m/z 362 (M+H).

Intermediate 4: 2-(4-Bromo-2-fluorophenyl)acetic acid

Step 1: 2-(4-Bromo-2-fluorophenyl)acetonitrile

A suspension of NaCN (2.085 g, 42.5 mmol) in DMF (20 mL) was added to asolution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27 mmol)in DMF (20 mL). The mixture was stirred at 26° C. for 10 h. Then thesolution was concentrated and distributed between EA and saturatedNaHCO₃ solution. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The resulting2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol, 88.0% yield)was used to next step without further purification. TLC (PE/EA=1/1,R_(f) 0.5): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.37 (m, 3H), 3.70 (s, 2H).

Step 2: 2-(4-Bromo-2-fluorophenyl)acetic acid

NaOH (56.2 mL, 112 mmol) was added to a solution of2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) in MeOH (30mL). The mixture was stirred at 100° C. for 12 h. The mixture was cooledto rt. Then the solution was concentrated and distributed between EA andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated. The resulting2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95.0% yield)was used to next step without further purification. TLC (PE/EA=1/1,R_(f)=0.4): ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.31 (m, 2H), 7.13 (t, J=8.05Hz, 1H), 3.67 (s, 2H); ES-LCMS m/z 232.9 (M+H).

Intermediate 5: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

Step 1: 4-Ethoxypyridine 1-oxide

To a mixture of 4-nitropyridine 1-oxide (50 g, 357 mmol) in THF (500 mL)was added sodium ethanolate (48.6 g, 714 mmol). The mixture was stirredat 25° C. for 16 h. The reaction residue was concentrated. The crudematerial was purified by silica column chromatography (DCM/MeOH=25:1).All fractions found to contain product by TLC (DCM/MeOH=25:1, R_(f)=0.6)were combined and concentrated to yield a dark red solid of4-ethoxypyridine 1-oxide (25 g, 162 mmol, 45.3% yield): ¹H NMR (400 MHz,CD₃OD) δ 8.20-8.18 (m, 2H), 7.11-7.10 (m, 2H), 4.21-4.15 (m, 2H), 1.42(t, J=7.2 Hz, 3H); ES-LCMS m/z 140.0(M+H).

Step 2: 4-Ethoxypyridin-2-ol

A mixture of 4-ethoxypyridine 1-oxide (5 g, 35.9 mmol) in aceticanhydride (36.7 g, 359 mmol) was heated to reflux for 4 h. Then thesolvent was removed in vacuo, and the residue was dissolved in MeOH (25mL) and H₂O (25 mL) and stirred at 25° C. for 16 h. The mixture wasconcentrated. The crude material was purified by silica columnchromatography (DCM/MeOH=10:1). All fractions found to contain productby TLC (DCM/MeOH=10:1, R_(f)=0.6) were combined and concentrated toyield a dark yellow solid of 4-ethoxypyridin-2-ol (2.5 g, 16.17 mmol,45.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.28 (d, J=7.6 Hz, 1H), 6.07 (d,J=3.2, 7.2 Hz, 1H), 5.86-7.85 (d, J=2.4 Hz, 1H), 4.06-4.01 (m, 2H), 1.38(t, J=7.2 Hz, 3H); ES-LCMS m/z 140.0 (M+H).

Step 3: 4-Ethoxy-5-iodopyridin-2-ol

To a mixture of 4-ethoxypyridin-2-ol (2.5 g, 17.97 mmol) in DMF (30 mL)was added NIS (4.04 g, 17.97 mmol). The mixture was stirred at 80° C.for 16 h. The mixture was concentrated and purified by preparative HPLC(MeCN/H₂O as eluants, acidic condition) to yield a yellow solid of4-ethoxy-5-iodopyridin-2-ol (1.2 g, 4.30 mmol, 23.9% yield): ¹H NMR (400MHz, CD₃OD) δ 7.70 (s, 1H), 5.92 (s, 1H), 4.15-4.10 (m, 2H), 1.48 (t,J=6.8 Hz, 3H); ES-LCMS m/z 265.8 (M+H).

Step 4: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

To a mixture of 4-ethoxy-5-iodopyridin-2-ol (800 mg, 3.02 mmol) in THF(10 mL) was added (bromomethyl)benzene (619 mg, 3.62 mmol) and silvercarbonate (1665 mg, 6.04 mmol). The mixture was stirred at 70° C. for 16h. The reaction residue was filtered and the filtrate was concentrated.The mixture was diluted with H₂O and extracted with DCM. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The resulting 2-(benzyloxy)-4-ethoxy-5-iodopyridine (800mg, 1.915 mmol, 63.4% yield) was used to next step without furtherpurification: ¹H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.45-7.43 (m, 2H),7.38-7.36 (m, 3H), 6.22 (s, 1H), 5.33 (s, 2H), 4.12-4.07 (m, 2H), 1.48(t, J=6.8 Hz, 3H); ES-LCMS m/z 355.9 (M+H).

Intermediate 6: 5-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-3-amine

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxopentanenitrile

To a mixture of MeCN (3.32 mL, 97 mmol) in THF (300 mL) cooled to −78°C. was added n-BuLi (56.4 mL, 141 mmol). The mixture was stirred at −30°C. for 30 min. Then to the mixture was added methyl3,3,3-trifluoro-2,2-dimethylpropanoate (15 g, 88 mmol) dropwise. Themixture was stirred at 25° C. for 10 h. The mixture was quenched withaqueous NH₄Cl and extraced with DCM/MeOH (10:1). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude material waspurified by silica column chromatography (PE/EA=10:1). All fractionsfound to contain product by TLC (PE/EA=5:1, R_(f)=0.6) were combined andconcentrated to yield a light yellow solid of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (5 g, 27.9 mmol, 31.7%yield): ¹H NMR (400 MHz, CDCl₃) δ: 3.75 (s, 2H), 1.41 (s, 6H).

Step 2: 5-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-3-amine

To a mixture of hydroxylamine hydrochloride (3.10 g, 44.7 mmol) in H₂O(25 mL) cooled to 0° C. was added NaHCO₃ (3.94 g, 46.9 mmol) to adjustto pH=7.5. Then to the mixture was added a solution of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (4 g, 22.33 mmol) inMeOH (25 mL). The mixture was stirred at 65° C. for 15 h. After cooled,the mixture was acified with conc. HCl to pH=1.0 and then refluxed for 2h. After cooling, the mixture was neutralized by 4 M NaOH to pH=8.0. Themixture was extracted with DCM/MeOH (10:1). The organic layer was driedover Na₂SO₄, filtered and concentrated to yield a white solid of5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (2 g, 9.06 mmol,40.6% yield): ¹H NMR (400 MHz, CDCl₃) δ 5.78 (s, 1H), 3.93 (s., 2H),1.51 (s, 6H); ES-LCMS m/z 195 (M+1).

Intermediate 7: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Step 1: 4-Methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole

A suspension of 4-methyl-1H-imidazole (1.178 g, 14.35 mmol) in DMF (15mL) was added to a solution of1-fluoro-3-nitro-5-(trifluoromethyl)benzene (2 g, 9.56 mmol) in DMF (15mL). Cs₂CO₃ (6.23 g, 19.13 mmol) was added and the mixture was stirredat 80° C. for 8 h. The mixture was cooled to rt and then the solutionwas concentrated and distributed between EA and saturated NaHCO₃solution. The combined organic extract was washed with brine, dried overMgSO₄, filtered and concentrated. The crude material was purified bysilica column chromatography (PE/EA=5:1). All fractions found to containproduct by TLC (PE/EA=1:1, R_(f)=0.5) were combined and concentrated toyield a light yellow solid of4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg,2.95 mmol, 30.8% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.78 (m, 1H),8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H);ES-LCMS m/z 272.0 (M+H).

Step 2: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

A suspension of4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg,2.95 mmol) in MeOH (15 mL) was added to a solution of Pd/C (8.26 mg,0.078 mmol) in MeOH (15 mL). The mixture was at 25° C. for 5 h under H₂atmosphere. Then the solution was concentrated and distributed betweenEA and saturated NaHCO₃ solution. The combined organic extract waswashed with brine, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by preparative HPLC (MeCN/H₂O as eluants,basic condition) to yield a white solid of3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (321.83 mg,1.334 mmol, 86.0% yield). TLC (PE/EA=1:1, R_(f)=0.3): ¹H NMR (400 MHz,CD₃OD) δ 7.98 (s, 1H), 7.24 (s, 1H), 7.02-6.76 (m, 3H), 2.31-2.17 (m,3H); ES-LCMS m/z 242.1 (M+H).

Intermediate 8: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (4 g, 24.53mmol) in H₂SO₄ (26.1 mL, 491 mmol) was added nitric acid (1.206 mL, 27.0mmol) dropwise. After 30 min, the ice bath was removed and the reactionwas stirred at 26° C. for 10 h. The reaction mixture was added to 120 gice. The resulting precipitate was collected by filtration, rinsed withadditional H₂O and air-dried to afford the first batch of product.Another crop of product was obtained after evaporating the mother liquorto less than 100 mL, cooling on an ice bath, and adding NaOH to adjustto pH=8. The mixture was extracted by EA (100 mL). The organic layer wasdried and concentrated to give the product, which was combined with thefirst batch to yield a yellow solid of5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol, 51.5%yield): ¹H NMR (400 MHz, CD₃OD) δ: 8.86 (d, J=3.1 Hz, 1H), 8.55 (d,J=2.6 Hz, 1H); ES-LCMS m/z 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

SOCl₂ (18.45 mL, 253 mmol) was added to a solution of5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957mL, 25.3 mmol) was added and the mixture was at 100° C. for 10 h. Thenthe solution was concentrated and distributed between EA and saturatedNaHCO₃ solution. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The resulting2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86%yield) was used in the next step without further purification. TLC(PE/EA=5:1, R_(f)=0.6): ¹H NMR (400 MHz, CDCl₃) δ: 9.23-9.59 (m, 1H),8.79 (d, J=2.4 Hz, 1H).

Step 3: tert-Butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of tert-butyl 2-cyanoacetate (523 mg, 3.71 mmol) in THF(15 mL) was added K₂CO₃ (854 mg, 6.18 mmol). Then2-chloro-5-nitro-3-(trifluoromethyl)pyridine (700 mg, 3.09 mmol) wasadded into the mixture and the mixture was at 50° C. for 10 h. Then thesolution was concentrated and distributed between EA and saturatedNaHCO₃ solution. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The crude material waspurified by preparative TLC (DCM/MeOH=20:1, R_(f)=0.4) to yield a lightyellow solid of tert-butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (1 g, 3.02mmol, 98.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.99 (d, J=2.43 Hz, 1H),8.36 (d, J=2.43 Hz, 1H), 3.35 (s, 1H), 1.49 (d, J=1.54 Hz, 9H); ES-LCMSm/z 276 (M-55).

Step 4: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

To a solution of tert-butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (1.06 g, 3.20mmol) in MeOH (80 mL) was added HCl (20 mL, 3.20 mmol). The mixture wasat 70° C. for 10 h. Then the solution was concentrated and distributedbetween EA and saturated NaHCO₃ solution. The combined organic extractwas washed with brine, dried over MgSO₄, filtered and concentrated. Theresulting 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (402mg, 1.739 mmol, 54.4% yield) was used in the next step without furtherpurification. TLC (PE/EA=5:1, R_(f)=0.6): ¹H NMR (400 MHz, CDCl₃) δ 9.56(d, J=2.21 Hz, 1H), 8.63-8.87 (m, 1H), 4.20 (br. s., 2H); ES-LCMS m/z232.0 (M+H).

Intermediate 9:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

Step 1:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid

A suspension of 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287mmol) in 1,4-dioxane (3 mL) and H₂O (1.000 mL) was added to a solutionof3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(496 mg, 1.287 mmol) in 1,4-dioxane (3 mL) and H₂O (1.000 mL).PdCl₂(dppf) (94 mg, 0.129 mmol) and Cs₂CO₃ (1049 mg, 3.22 mmol) wereadded and the mixture was stirred at 110° C. for 30 min under microwaveirradiation. The mixture was cooled to rt and then the solution wasconcentrated and distributed between EA and saturated NaHCO₃ solution.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative TLC (PE/EA=1:1, R_(f)=0.5) to yield a light yellow solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (320 mg, 0.778 mmol, 60.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.93(d, J=1.8 Hz, 1H), 7.18-7.50 (m, 6H), 6.78-7.00 (m, 2H), 5.28-5.54 (m,2H), 4.04-4.21 (m, 2H), 3.74-3.84 (m, 3H), 3.30-3.38 (m, 2H), 1.32-1.52(m, 3H); ES-LCMS m/z 412.0 (M+H).

Step 2:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

A suspension of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (120 mg, 0.292 mmol) in MeOH (10 mL) was added to a solution ofPd/C (31.0 mg, 0.292 mmol) in MeOH (10 mL). The mixture was stirredunder a H₂ atmosphere at 26° C. for 2 h. Then the solution was filteredand concentrated. The crude material was purified by preparative HPLC(MeCN/H₂O as eluants, acidic condition) to yield a light yellow solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(80 mg, 0.275 mmol, 94.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.14-7.53(m, 5H), 4.01-4.21 (m, 2H), 3.60-3.68 (m, 2H), 1.46 (s, 3H); ES-LCMS m/z292.1 (M+H).

Intermediate 10:4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine

Step 1:(4-Amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone

A mixture of 4-amino-2-trifluoromethyl-benzoic acid (15 g, 73.1 mmol),HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et₃N (20.38 mL, 146mmol), 1-ethyl-piperazine (8.35 g, 73.1 mmol) in DCM (200 mL) wasstirred at 25° C. for 2 h. To the mixture was added DCM (200 mL) andthen washed with H₂O, 2 M NaOH (2×150 mL) and brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated to give a off whitesolid of(4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone(20 g, 65.2 mmol, 89.0% yield): ¹H NMR (400 MHz, CDCl₃) δ: 7.07 (d,J=8.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.0, 8.0 Hz, 1H),3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H),2.33-2.31 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).

Step 2: 4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine

To a mixture of(4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone(20 g, 66.4 mmol) in THF (500 mL) was added BH₃.DMS (19.91 mL, 199 mmol)dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixturewas quenched by adding MeOH and then concentrated. The residue waspurified by silica column chromatography on silica gel (PE:EA=2:1,R_(f)=0.35) to give a white solid of4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g,46.0 mmol, 69.4% yield): ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J=8.4 Hz,1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H),3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288(M+H).

Intermediate 11:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid

Step 1: 2-Chloro-4-ethoxypyridine

To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L)was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0° C. Themixture was stirred at 25° C. for 12 h. LCMS and TLC (PE/EA=5:1,R_(f)=0.6) showed the reaction was finished. The mixture was filtered,and most solvent of the filtrate was removed in vacuo. The residue wasextracted with EA (800 mL×3), and the organic layer was washed withsaturated NaCl solution (1 L), dried over Na₂SO₄, filtered, andconcentrated to give crude 2-chloro-4-ethoxypyridine (157 g, 1.0 mol,92% yield) as a solid: ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=6.0 Hz, 1H),6.99 (d, J=2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38(m, 3H); ES-LCMS m/z 158 (M+H).

Step 2: 5-Bromo-2-chloro-4-ethoxypyridine

2-Chloro-4-ethoxypyridine (100 g, 0.63 mol) was added to H₂SO₄ (500 mL)slowly. Then 1-bromopyrrolidine-2,5-dione (124.2 g, 0.70 mol) was addedinto above mixture at rt. The mixture was stirred at 80° C. for 3 h. TLC(PE/EA=10:1, R_(f)=0.5) showed the reaction was finished. The reactionmixture was poured into ice-water (2 L), and extracted with EA (1 L×3).The organic layer was washed with saturated Na₂CO₃ solution (1 L×2),dried over Na₂SO₄ and concentrated. The residue was purified by silicacolumn chromatography (PE/EA=60:1-30:1). All fractions found to containproduct by TLC (PE/EA=10:1, R_(f)=0.5) were combined and concentrated toyield 5-bromo-2-chloro-4-ethoxypyridine (60.9 g, 0.26 mol, 40% yield):¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.14 (s, 1H), 4.32-4.10 (m, 2H),1.58-1.35 (m, 3H); ES-LCMS m/z 237 (M+2).

Step 3: 5-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (75 g, 317.1 mmol) intoluene (500 mL) was added (4-methoxyphenyl)methanol (52.6 g, 380.6mmol), KOH (35.6 g, 634.3 mmol) and 18-crown-6 (8.4 g, 31.2 mmol) at rt.The reaction mixture was stirred at 120° C. for 2 h. The mixture wasportioned between 2-methoxy-2-methylpropane (500 mL) and brine (800 mL).The organic layer was concentrated. The residue was purified by column(PE/EA=10:1, R_(f)=0.5) to give5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (72.2 g, 221 mmol, 70%yield): ¹H NMR (400 MHz, CD₃OD) δ 8.05 (s, 1H), 7.33 (d, J=8.8 Hz, 2H),6.90-6.84 (m, 2H), 6.38 (s, 1H), 5.20 (s, 2H), 4.16-4.05 (m, 2H), 3.77(s, 3H), 1.43 (q, J=6.8 Hz, 3H); ES-LCMS m/z 338 (M+2H).

Step 4: 2-(4-Bromo-2-fluorophenyl)acetonitrile

To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (500 g, 1.87mol) in EtOH (2.2 L) stirred under nitrogen at 20° C. was added NaCN (93g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60° C.for 12 h. Then the solution was concentrated and distributed between DCM(2000 mL) and saturated NaHCO₃ solution (1800 mL). Another batch wasrepeated using the same procedure. Then the two batches were combined.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated to provide2-(4-bromo-2-fluorophenyl)acetonitrile (794 g, 99% yield): ¹H NMR (400MHz, CDCl₃) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).

Step 5: 2-(4-Bromo-2-fluorophenyl)acetic acid

To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (397 g, 1.82mol) in MeOH (500 mL) stirred under nitrogen at 20° C. was added NaOH(2.22 L, 2.5M, 5.56 mol) solution in one charge. The reaction mixturewas stirred at 80° C. for 5 h. Then the solution was concentrated andneutralized with conc. HCl to pH=5 with stirring. Then the solution wasextracted with EA (1.5 L×2). Another two batches were repeated using thesame procedure. Then the three batches were combined. The combinedorganic extract was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to give the pure 2-(4-bromo-2-fluorophenyl)aceticacid (1200 g, 92% yield): TLC (PE/EA=5:1, R_(f)=0.2); ¹H NMR (400 MHz,CDCl₃) δ 7.24 (br. s., 1H), 7.12 (t, J=7.9 Hz, 1H), 3.65 (s, 2H).

Step 6: Methyl 2-(4-bromo-2-fluorophenyl)acetate

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (260 g, 1.13 mol)in MeOH (2 L) was added H₂SO₄ (30 mL) at rt. The solution was heated toreflux overnight. Then the solvent was concentrated and distributedbetween EA and saturated NaHCO₃ solution. The combined organic extractwas washed with brine, dried over Na₂SO₄, filtered and concentrated.Another batch was repeated using the same procedure. Then the twobatches were combined to provide methyl2-(4-bromo-2-fluorophenyl)acetate (520 g, 94%). TLC (PE/EA=10:1,R_(f)=0.7). ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.20 (m, 2H), 7.14 (t, J=8.0Hz, 1H), 3.70 (s, 3H), 3.62 (s, 2H).

Step 7: Methyl2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-fluorophenyl)acetate (260 g, 1.05mol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(320 g, 1.26 mol) in 1,4-dioxane (2 L) was added KOAc (206 g, 2.10 mol)and PdCl₂(dppf) (23 g, 0.03 mol) at rt. The solution was heated toreflux for 4 h under N₂. Then the solution was filtered and the filtratewas concentrated in vacuo to give the crude product. Another batch wasrepeated using the same procedure. Then the two batches were combinedand purified by silica column chromatography (PE/EA=30:1 to 10:1). Allfractions found to contain product by TLC (PE/EA=10:1, R_(f)=0.5) werecombined and concentrated to yield methyl2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(560 g, 90%) as a light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d,J=7.5 Hz, 1H), 7.49 (d, J=10.0 Hz, 1H), 7.31-7.26 (m, 1H), 3.73 (s, 2H),1.34 (s, 12H), 1.27 (s, 3H); ES-LCMS m/z 295.2 (M+H).

Step 8: Methyl2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate

To a solution of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (175g, 519 mmol) in 1,4-dixoane (1.2 L) and H₂O (300 mL) was added methyl2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(167 g, 569 mmol), PdCl₂(dppf) (25 g, 5.19 mmol) and Cs₂CO₃ (337 g, 1038mmol) under N₂. The mixture was refluxed for 2 h. TLC (PE/EA=5:1,R_(f)=0.3) showed the reaction was finished. The mixture was portionedbetween EA (1 L) and H₂O (800 mL). The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography (PE/EA=5:1, R_(f)=0.3) to give5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (210 g, 0.49 mol, 90%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H), 7.36 (d, J=8.8 Hz, 2H),7.32-7.22 (m, 3H), 6.90 (d, J=8.8 Hz, 2H), 6.43 (s, 1H), 5.26 (s, 2H),4.11 (d, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.70 (s, 3H), 1.36(t, J=7.2 Hz, 3H); ES-LCMS m/z 426 (M+H).

Step 9:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid

To a solution of methyl2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate(210 g, 519 mmol) in THF (500 mL) was added a solution of LiOH.H₂O (52g, 1.23 mol) in H₂O (700 mL). The mixture was stirred at 60° C. for 10h. TLC (PE/EA=5:1, R_(f)=0.3) showed the reaction was finished. Themixture was concentrated and neutralized with 1.0 M HCl to pH=7.0. Thenthe mixture was filtered, and the solid was washed with water and dry invacuo to give2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (183.3 g, 0.45 mol, 93% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s,1H), 7.41-7.28 (m, 3H), 7.24 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H),6.44 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.67(s, 2H), 1.36 (t, J=7.2 Hz, 3H); ES-LCMS m/z 412 (M+H).

Intermediate 12:2-(4-Bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

Step 1: 2-(4-Bromo-2-fluorophenyl)acetonitrile

To a suspension of NaCN (2.085 g, 42.5 mmol) in DMF (20 mL) was added toa solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27mmol) in DMF (20 mL). The mixture was stirred at 26° C. for 10 h. Thenthe solution was concentrated and partioned between EA (50 mL) andsaturated NaHCO₃ solution (50 mL). The organic extract was washed withbrine (50 mL), dried over MgSO₄, filtered and concentrated to give a offwhite solid of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74mmol, 88% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.37 (m, 3H), 3.70 (s,2H).

Step 2: 2-(4-Bromo-2-fluorophenyl)acetic acid

To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74mmol) in MeOH (30 mL) was added 2 M NaOH (56.2 mL, 112 mmol). Themixture was stirred at 100° C. for 12 h. The mixture was then cooled tort. Then the solution was concentrated and distributed between EA andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated to provide2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95% yield):¹H NMR (400 MHz, CDCl₃) δ 7.31-7.22 (m, 2H), 7.13 (t, J=8.05 Hz, 1H),3.67 (s, 2H); ES-LCMS m/z 233 (M+H).

Step 3: 5,5,5-Trifluoro-4,4-dimethyl-3-oxopentanenitrile

To a mixture of MeCN (1.086 g, 26.5 mmol) in THF (300 mL) cooled to −78°C. was added n-BuLi (10.58 mL, 26.5 mmol). The mixture was stirred at−30° C. for 0.5 h. Then to the mixture was added methyl3,3,3-trifluoro-2,2-dimethylpropanoate (3 g, 17.63 mmol) dropwise. Themixture was quenched with aqueous NH₄Cl and extracted with DCM/MeOH(10:1, 30 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by silica columnchromatography (PE/EA=8:1). All fractions found to contain product byTLC (PE/EA=5:1, R_(f)=0.5) were combined and concentrated to yield alight yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1g, 5.30 mmol, 30% yield): ¹H NMR (400 MHz, CDCl₃) δ 3.79 (s, 2H), 1.41(s, 6H).

Step 4: 3-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-5-amine

To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g,5.58 mmol) and hydroxylamine hydrochloride (0.407 g, 5.86 mmol) in water(30 mL) was added NaOH (0.447 g, 11.16 mmol). Then the mixture wasstirred at 100° C. for 3 h. After cooling to rt, the mixture wasextracted with DCM (50 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated to yield a light yellow solid of3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (700 mg, 3.39mmol, 61% yield): ¹H NMR (400 MHz, CDCl₃) δ 5.17 (s, 1H), 4.41 (s, 2H),1.49 (s, 6H); ES-LCMS m/z 195 (M+H).

Step 5:2-(4-Bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545mmol) in DCM (50 mL) was added3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (300 mg, 1.545mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture waswashed with brine (50 mL), dried over Na₂SO₄, filtered, and concentratedto yield a yellow oil of2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(600 mg, 1.1 mmol, 71% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=6.8Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (s, 1H), 6.64 (d, J=6.8 Hz, 1H), 6.43(s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 (M+H).

Preparation of Compounds of the Invention Example 12-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Step 1: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a mixture of 3-(trifluoromethyl)pyridin-2-ol (2 g, 12.26 mmol) wasadded nitric acid (1.644 mL, 36.8 mmol) and H₂SO₄ (12.03 g, 123 mmol) at0° C. Then the mixture was stirred at 25° C. for 16 h. The mixture wasthen warmed to 60° C. for 5 h, cooled and added to 150 g of ice. Themixture was extracted with EA (2×100 mL) and washed with H₂O (100 mL) togive the organic layer. The combined organic extract was washed withbrine, dried over Na₂SO₄, concentrated to yield a brown solid of5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.2 g, 8.99 mmol, 73.3% yield):¹H NMR (400 MHz, CD₃OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42 (d, J=2.43 Hz,1H); ES-LCMS m/z 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2 g, 9.61 mmol)was added SOCl₂ (21.04 mL, 288 mmol) and DMF (0.074 mL, 0.961 mmol).Then the mixture was stirred at 80° C. for 16 h. The mixture wasconcentrated and extracted with EA (2×100 mL) and washed with H₂O (100mL) to give the organic layer. The combined organic extract was washedwith brine, dried over Na₂SO₄, concentrated to yield a brown solid of2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 5.30 mmol, 55.1%yield): ¹HNMR (400 MHz, CD₃OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42 (d,J=2.43 Hz, 1H).

Step 3: 6-Chloro-5-(trifluoromethyl)pyridin-3-amine

To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83mmol) in acetic acid (10 mL) was added iron (2.465 g, 44.1 mmol) in oneportion. The mixture was stirred at 80° C. for 15 min. The mixture wasfiltered and concentrated and then washed with aqueous NaOH andextracted with EA. The crude material was purified by silica columnchromatography (PE/EA=5:1). All fractions found to contain product byTLC (PE/EA=8:1, R_(f)=0.6) were combined and concentrated to yield ayellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 4.58mmol, 51.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 7.86 (d,J=8.60 Hz, 1H), 7.53 (d, J=8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11(m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).

Step 4: 1-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)ethanone

To a mixture of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (200 mg,1.018 mmol) in MeOH (3 mL) was added6-chloro-5-(trifluoromethyl)pyridin-3-amine (200 mg, 1.018 mmol), NaHCO₃(171 mg, 2.035 mmol) and PdCl₂(dppf) (74.5 mg, 0.102 mmol). The mixturewas stirred under a N₂ atmosphere at 110° C. for 30 min under microwave.Then the reaction residue was filtered and the solid was washed by MeOH.Then 6M HCl was added to the solution, which was stirred a rt for 1 hand then concentrated to give the crude product. The crude product waspurified by preparative TLC (PE/EA=1:1, R_(f)=0.6) to yield a lightyellow solid of 1-(5-amino-3-(trifluoromethyl)pyridin-2-yl)ethanone (120mg, 0.500 mmol, 49.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.43Hz, 1H), 7.30 (d, J=2.43 Hz, 1H), 2.56 (s, 3H); ES-LCMS m/z 205.0 (M+H).

Step 5:N-(6-Acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide

To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (125 mg, 0.536mmol) in DCM (10 mL) was added 2-(4-bromo-2-fluorophenyl)acetic acid(125 mg, 0.536 mmol), EDC (123 mg, 0.644 mmol), HOBt (99 mg, 0.644 mmol)and Et₃N (0.150 mL, 1.073 mmol). The mixture was stirred at 25° C. for16 h. Then the reaction residue was concentrated to give the crudeproduct, which was purified by preparative TLC (PE/EA=1:1, R_(f)=0.6) toyield a light yellow solid ofN-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide(120 mg, 0.243 mmol, 45.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.00 (d,J=1.5 Hz, 1H), 8.60 (d, J=1.5 Hz, 1H), 8.13 (d, J=2.5 Hz, 2H), 7.33 (s.,1H), 3.85 (s, 2H), 2.66 (s, 3H); ES-LCMS m/z 418.9 (M+H).

Step 6:N-(6-Acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(100 mg, 0.260 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) was addedN-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide(120 mg, 0.286 mmol), Cs₂CO₃ (169 mg, 0.519 mmol) and PdCl₂(dppf) (18.99mg, 0.026 mmol). The mixture was stirred under a N₂ atmosphere at 110°C. for 30 min under microwave. Then the reaction residue was filteredand the filtrate was concentrated to give the crude product, which waspurified by preparative TLC (PE/EA=1:1, R_(f)=0.6) to yield a lightyellow solid ofN-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.100mmol, 38.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.02 (s, 1H), 8.62 (s,1H), 8.13 (d, J=2.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 4H), 7.33 (d, J=2.5 Hz,2H), 6.94 (s, 1H), 5.39 (s, 2H), 4.15-4.09 (m, 2H), 3.91 (s, 2H), 2.03(s, 3H), 1.26 (t, J=7.0 Hz, 3H); ES-LCMS m/z 598.1 (M+H).

Step 7:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a mixture ofN-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(100 mg, 0.167 mmol) in THF (10 mL) was added methylmagnesium bromide(0.167 mL, 0.502 mmol). The mixture was stirred at 0° C. for 2 h under aN₂ atmosphere. Then the mixture was added to H₂O and extracted with EA.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative TLC (DCM/MeOH=15:1, R_(f)=0.6) to yield a yellow solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide(70 mg, 0.086 mmol, 51.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.87 (d,J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.94 (d,J=2.0 Hz, 1H), 7.44-7.40 (m, 3H), 7.29 (d, J=2.4 Hz, 1H), 6.88 (s, 2H)6.78 (d, J=2.4 Hz, 1H), 5.35 (s, 2H), 4.17-4.11 (m, 2H), 3.83 (s, 2H),3.77 (s, 3H), 1.59 (s, 6H), 1.41 (t, J=7.1 Hz, 3H); ES-LCMS m/z 494.2(M-PMB+H).

Step 8:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide(70 mg, 0.114 mmol) in MeOH (10 mL) was added Pd/C (7 mg, 0.066 mmol).The mixture was stirred under a H₂ atmosphere at 25° C. for 16 h. Thenthe reaction residue was filtered and concentrated. The crude materialwas purified by preparative HPLC (MeCN/H₂O as eluants, basic condition)to yield a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridine-3-yl)acetamide (5.71 mg, 0.011 mmol, 10.9% yield): ¹H NMR (400 MHz, CD₃OD) δ8.90 (s, 1H), 8.48 (s, 1H), 7.48-7.43 (m, 1H), 7.40-7.32 (m, 3H), 7.26(d, J 2.01 Hz, 1H), 4.15 (m, 2H), 3.86 (s, 2H), 1.62 (s, 6H), 1.49 (t,J=7.03 Hz, 3H); ES-LCMS m/z 494.2 (M+H).

Example 2N-(6-Ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a mixture of 3-(trifluoromethyl)pyridin-2-ol (2 g, 12.26 mmol) andnitric acid (1.644 mL, 36.8 mmol) was added H₂SO₄ (12.03 g, 123 mmol) at0° C. Then the mixture was stirred at 25° C. for 16 h. The mixture wasthen warmed to 60° C. for 5 h, cooled and added to 150 g of ice. Themixture was extracted with EA (2×100 mL) and washed with H₂O (100 mL) togive the organic layer. The combined organic extract was washed withbrine, dried over Na₂SO₄, filtered, and concentrated to yield a brownsolid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.2 g, 8.99 mmol,73.3% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42(d, J=2.43 Hz, 1H); ES-LCMS m/z 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2 g, 9.61 mmol)and SOCl₂ (21.04 mL, 288 mmol) was added DMF (0.074 mL, 0.961 mmol).Then the mixture was stirred at 80° C. for 16 h. The mixture wasconcentrated and extracted with EA (2×100 mL) and washed with H₂O (100mL) to give the organic layer. The combined organic extract was washedwith brine, dried over Na₂SO₄, filtered, and concentrated to yield abrown solid of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 5.30mmol, 55.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.91 (d, J=2.43 Hz, 1H),9.42 (d, J=2.43 Hz, 1H).

Step 3: 2-Ethoxy-5-nitro-3-(trifluoromethyl)pyridine

To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg,2.207 mmol) in THF (10 mL) was added EtOH (0.155 mL, 2.65 mmol) and NaH(132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min,then warmed to rt and stirred for 16 h. The mixture was added to

H₂O and extracted with EA (2×50 mL) to give the organic layer. Thecombined organic extract was washed with brine, dried over Na₂SO₄,filtered, and concentrated to yield a brown oil of2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7%yield): ¹H NMR (400 MHz, CD₃OD) δ 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).

Step 4: 6-Ethoxy-5-(trifluoromethyl)pyridin-3-amine

To a mixture of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg,0.508 mmol) in EA (10 mL) was added tin(II) chloride dihydrate (459 mg,2.033 mmol). The mixture was stirred at 50° C. for 16 h. Then thesolution was distributed between EA and saturated NaHCO₃ solution. Thecombined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative TLC (PE/EA=4:1, R_(f)=0.6) to yield a light yellow oil of6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (80 mg, 0.310 mmol, 61.1%yield): ¹H NMR (400 MHz, CD₃OD) δ 6.27 (d, J=2.5 Hz, 1H), 5.86 (d, J=3.0Hz, 1H), 2.81 (m, 2H), 0.17 (t, J=7.0 Hz, 3H); ES-LCMS m/z 207.1 (M+H).

Step 5:2-(4-Bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (90 mg, 0.386mmol) in DCM (10 mL) was added6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (88 mg, 0.425 mmol), DIEA(0.135 mL, 0.772 mmol) and HATU (220 mg, 0.579 mmol). The mixture wasstirred at 25° C. for 16 h. The mixture was diluted with H₂O andextracted with DCM. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The crude material waspurified by preparative TLC (PE/EA=1:1, R_(f)=0.6) to yield a lightyellow oil of2-(4-bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide(120 mg, 0.228 mmol, 59.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d,J=2.0 Hz, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.39-7.34 (m, 3H), 4.47 (m, 2H),1.21 (t, J=6.5 Hz, 3H); ES-LCMS m/z 421.0 (M+H).

Step 6:N-(6-Ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(100 mg, 0.260 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) was added2-(4-bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide(120 mg, 0.286 mmol), Cs₂CO₃ (169 mg, 0.519 mmol) and PdCl₂(dppf) (18.99mg, 0.026 mmol). The mixture was stirred under a N₂ atmosphere at 110°C. for 30 min under microwave. Then the reaction residue was filteredand the filtrate was concentrated to give the crude product, which waspurified by preparative TLC (PE:EA=1:1, R_(f)=0.6) to yield a lightyellow solid ofN-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.071mmol, 27.3% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=2.5 Hz, 1H),8.29 (d, J=2.5 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.52-7.35 (m, 6H), 6.93(d, J=8.5 Hz, 2H), 5.39 (s, 2H), 4.47 (m, 2H), 4.17 (m, 2H), 3.78-3.85(m, 5H), 1.42-1.47 (m, 3H), 1.38-1.42 (m, 3H); ES-LCMS m/z 600.1 (M+H).

Step 7:N-(6-Ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

To a mixture ofN-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(40 mg, 0.067 mmol) in DCM (10 mL) was added TFA (0.701 mL, 9.10 mmol).The mixture was stirred at 25° C. for 2 h. Then the reaction residue wasadded to NaOH (2.5 m, 3 mL) and concentrated. The crude material waspurified by preparative HPLC (MeCN/H₂O as eluants, basic condition) toyield a white solid ofN-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (15.66 mg, 0.030 mmol, 49.8% yield): ¹H NMR (400 MHz,CD₃OD) δ 8.50 (s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 1H),7.40-7.31 (m, 3H), 7.26 (d, J=2.0 Hz, 1H), 4.47 (m, 2H), 4.15 (m, 2H),3.82 (s, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMSm/z 480.2 (M+H).

Example 32-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: Ethyl3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

Ethyl-3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (200mg, 0.691 mmol) was added to a solution of2-(4-bromo-2-fluorophenyl)acetic acid (161 mg, 0.691 mmol), HATU (315mg, 0.830 mmol) and TEA (0.482 mL, 3.46 mmol) in DCM (5 mL). Thereaction mixture was stirred at rt for 2 h, and then the solution wasdistributed between DCM and H₂O. The combined organic extract was driedover MgSO₄, filtered and concentrated. The crude product was purified bypreparative TLC (DCM, R_(f)=0.5) to yield a light yellow oil of ethyl3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(320 mg, 0.571 mmol, 83.0% yield): ¹H NMR (400 MHz, MeOH-d₄) δ 7.94 (d,J=1.54 Hz, 1H), 7.68 (d, J=8.38 Hz, 1H), 7.27-7.36 (m, 2H), 7.22 (d,J=8.38 Hz, 1H), 6.90-6.97 (m, 1H), 4.09-4.18 (m, 2H), 3.74 (s, 2H), 3.07(s, 2H), 1.20-1.25 (m, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M+H).

Step 2: Ethyl3-(4-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

PdCl₂(dppf) (23.21 mg, 0.032 mmol) was added to a solution of ethyl3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(320 mg, 0.635 mmol), KOAc (187 mg, 1.904 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (193 mg,0.761 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at100° C. for 8 h. Then the solution was concentrated and distributedbetween EA and H₂O. The combined organic extract was washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude material waspurified by preparative TLC (PE/EA=5:1, R_(f)=0.6) to yield a lightyellow oil of ethyl3-(4-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(300 mg, 0.490 mmol, 77% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H),7.68 (d, J=8.60 Hz, 1H), 7.50 (d, J=7.50 Hz, 1H), 7.33-7.41 (m, 2H),7.22 (d, J=8.60 Hz, 1H), 4.12-4.15 (m, 2H), 3.78 (s, 2H), 3.07 (s, 2H),1.33 (s, 12H), 1.22 (d, J=1.54 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 552(M+H).

Step 3: Ethyl3-(4-(2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

The reaction mixture of PdCl₂(dppf) (13.27 mg, 0.018 mmol),4-(benzyloxy)-2-ethoxy-1-iodobenzene (0.131 mL, 0.399 mmol), ethyl3-(4-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (0.121 mL, 0.363 mmol) and Cs₂CO₃ (355 mg, 1.088 mmol) in H₂O(1 mL) and 1,4-dioxane (3 mL) was stirred at 100° C. for 2 h. Then thesolution was concentrated and distributed between DCM and H₂O. Thecombined organic extract was dried over MgSO₄, filtered andconcentrated. The crude material was purified by silica columnchromatography (PE/EA=5:1). All fractions found to contain product byTLC (PE/EA=2:1, R_(f)=0.6) were combined and concentrated to yield alight yellow oil of ethyl3-(4-(2-(4′-(benzyloxy)-2′-ethoxy-3-fluoro-[1,11-biphenyl]-4-yl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(100 mg, 0.147 mmol, 40.6% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.93-7.98(m, 2H), 7.71 (dd, J=8.49, 1.87 Hz, 1H), 7.42-7.46 (m, 2H), 7.32-7.39(m, 3H), 7.25-7.31 (m, 3H), 7.23 (d, J=8.60 Hz, 1H), 6.48 (s, 1H), 5.35(s, 2H), 4.10-4.17 (m, 4H), 3.79 (s, 2H), 3.07 (s, 2H), 2.00 (s, 2H),1.23 (dd, J=7.17, 0.88 Hz, 6H), 1.15 (s, 6H); ES-LCMS m/z 653 (M+H).

Step 4:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

LAH (17.45 mg, 0.460 mmol) was added to a solution of ethyl3-(4-(2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(100 mg, 0.153 mmol) in THF (5 mL). The reaction mixture was stirred at25° C. for 1 h. The reaction was then extracted with EA (50 mL), washedwith water and NaOH solution and dried over Na₂SO₄. The combined organicextracts were purified by preparative TLC (PE/EA=2:1, R_(f)=0.4) toyield a light yellow oil of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(20 mg, 0.032 mmol, 20.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.94-8.03(m, 2H) 7.77 (d, J=8.53 Hz, 1H) 7.46 (t, J=7.53 Hz, 3H) 7.36-7.43 (m,3H) 7.27-7.35 (m, 3H) 6.52 (s, 1H) 5.38 (s, 2H) 3.83 (s, 2H) 2.81 (s,2H) 2.03 (s, 4H) 1.40 (t, J=6.78 Hz, 3H) 1.26 (t, J=7.28 Hz, 3H)0.82-0.90 (m, 6H); ES-LCMS m/z 611 (M+H).

Step 5:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

The reaction mixture of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(20 mg, 0.033 mmol) and Pd/C (3.49 mg, 0.033 mmol) in MeOH (3 mL) wasstirred at 20° C. for 20 min under a H₂ atmosphere. Then the solutionwas concentrated and purified by preparative HPLC (MeCN/H₂O as eluants,acidic condition) to yield a white solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(11.88 mg, 0.022 mmol, 67.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d,J=1.98 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J=8.49, 1.87 Hz, 1H), 7.40-7.46(m, 2H), 7.25-7.32 (m, 2H), 6.37 (s, 1H), 4.24 (q, J=6.84 Hz, 2H), 3.82(s, 2H), 3.35 (br. s., 2H), 2.77 (s, 2H), 1.41 (t, J=6.95 Hz, 3H), 0.83(s, 6H); ES-LCMS m/z 521 (M+H).

Example 42-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-2,3-difluorophenyl)methanol

To a solution of 4-bromo-2,3-difluorobenzoic acid (650 mg, 2.74 mmol) inTHF (5 mL) stirred under N₂ at 0° C. was added BH₃DMS (1.371 mL, 13.71mmol) in one charge. The reaction mixture was stirred at 67° C. for 2 h.To the solution was added MeOH (5 mL) at rt. Then the solution wasstirred at rt for 30 min. The solution was concentrated in vacuo to givethe crude product. The resulting (4-bromo-2,3-difluorophenyl)methanol(600 mg, 1.749 mmol, 63.8% yield) was used in the next step withoutfurther purification. TLC (PE/EA=2:1, R_(f) 0.6): ¹H NMR (400 mHz,CDCl₃) δ 7.37-7.28 (m, 1H), 7.12 (t, J=7.4 Hz, 1H), 4.76 (d, J=5.2 Hz,2H), 3.70 (s, 1H).

Step 2: 1-Bromo-4-(bromomethyl)-2,3-difluorobenzene

To a solution of (4-bromo-2,3-difluorophenyl)methanol (500 mg, 2.242mmol) in DCM (10 mL) stirred under N₂ at 0° C. was added PBr₃ (0.634 mL,6.73 mmol) in one charge. The reaction mixture was stirred at 10° C. for2 h. Then the solution was concentrated and distributed between DCM andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by preparative TLC (PE/EA=10:1, R_(f) 0.6) to yield lightyellow oil of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154mmol, 51.5% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.30 (ddd, J=2.0, 6.0, 8.2Hz, 1H), 7.11-7.03 (m, 1H), 4.46 (s, 2H).

Step 3: 2-(4-Bromo-2,3-difluorophenyl)acetonitrile

To a solution of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg,1.154 mmol) in EtOH (10 mL) stirred under N₂ at 0° C. was added NaCN(73.5 mg, 1.500 mmol) in one charge. The reaction mixture was stirred at10° C. for 12 h. Then the solution was concentrated and distributedbetween EA and saturated NaHCO₃ solution. The combined organic extractwas washed with brine, dried over MgSO₄, filtered and concentrated. Theresulting 2-(4-bromo-2,3-difluorophenyl)acetonitrile was used in thenext step without further purification. TLC (PE/EA=5:1, R_(f) 0.6): ¹HNMR (400 MHz, CDCl₃) δ 7.39 (ddd, J=1.8, 6.1, 8.2 Hz, 1H), 7.15 (t,J=6.8 Hz, 1H), 3.78 (s, 2H).

Step 4: 2-(4-Bromo-2,3-difluorophenyl)acetic acid

Compound 2-(4-bromo-2,3-difluorophenyl)acetonitrile (200 mg, 0.690 mmol)was dissolved in H₂O (1 mL) and H₂SO₄ (1 mL) at 20° C. in one charge.The reaction mixture was stirred at 100° C. for 1 h. Then the solutionwas distributed between EA and H₂O. The combined organic extract waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresulting 2-(4-bromo-2,3-difluorophenyl)acetic acid (180 mg, 0.287 mmol,41.6% yield) was used in the next step without further purification. TLC(PE/EA=2:1, R_(f) 0.6): ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.20 (m, 1H),6.92-6.85 (m, 1H), 3.65 (s, 2H); ES-LCMS m/z 250.0 (M+H).

Step 5:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide

To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (20mg, 0.064 mmol), 2-(4-bromo-2,3-difluorophenyl)acetic acid (48.4 mg,0.077 mmol) and DIEA (0.034 mL, 0.193 mmol) in DCM (3 mL) stirred undera N₂ atmosphere at 20° C. was added HATU (29.3 mg, 0.077 mmol) in onecharge. The reaction mixture was stirred at 20° C. for 2 h. Then thesolution was distributed between DCM and saturated NaHCO₃ solution. Thecombined organic extract was washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude material was purified bypreparative TLC (PE/EA=5:1, R_(f) 0.3) to yield a light yellow solid ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide(12 mg, 0.019 mmol, 29.9% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.69-7.59(m, 2H), 7.36-7.24 (m, 6H), 7.05 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.4 Hz,1H), 4.64 (s, 2H), 4.20 (t, J=4.4 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.71(s, 2H); ES-LCMS m/z 546.0 (M+H).

Step 6:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide

To a solution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(8.49 mg, 0.022 mmol),N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide(12 mg, 0.022 mmol) and Cs₂CO₃ (17.96 mg, 0.055 mmol) in 1,4-dioxane (6mL) and H₂O (2 mL) stirred under a N₂ atmosphere at 20° C. was addedPdCl₂(dppf) (0.807 mg, 1.102 μmol) in one charge. The reaction vesselwas heated in 110° C. for 3 h. Then the solution was concentrated anddistributed between EA and saturated NaHCO₃ solution. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by preparative TLC(PE/EA=2:1, R_(f)=0.6) to yield a brown solid ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide(10 mg, 0.012 mmol, 52.7% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d,J=3.0 Hz, 1H), 7.66-7.50 (m, 2H), 7.41-7.34 (m, 2H), 7.29-7.07 (m, 8H),6.95-6.80 (m, 3H), 5.39 (d, J=4.9 Hz, 2H), 4.57 (d, J=5.0 Hz, 2H), 4.14(d, J=4.0 Hz, 2H), 4.09-3.96 (m, 2H), 3.84-3.66 (m, 7H), 1.38 (q, J=6.4Hz, 3H); ES-LCMS m/z 723.1 (M+H).

Step 7:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

To a solution ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide(10 mg, 0.014 mmol) in MeOH (3 mL) stirred under N₂ at 20° C. was addedPd/C (0.147 mg, 1.384 μmol) in one charge. The solution was stirredunder a H₂ atmosphere. The reaction mixture was stirred at 10° C. for 12h. The mixture was filtered, and the filtrate was concentrated in vacuoto give the crude product. The crude material was purified bypreparative HPLC (MeCN/H₂O as eluants, acidic condition) to yield alight yellow solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide (3.17 mg, 6.19 μmol, 44.7%yield). TLC (DCM/MeOH=5:1, R_(f)=0.4): ¹H NMR (400 MHz, CD₃OD) δ 7.88(d, J=2.4 Hz, 1H), 7.75 (dd, J=2.2, 8.8 Hz, 1H), 7.37-7.12 (m, 5H),4.20-4.07 (m, 4H), 3.90 (t, J=5.0 Hz, 2H), 3.85 (s, 2H), 1.48 (t, J=7.0Hz, 3H); ES-LCMS m/z 513.2 (M+H).

Example 52-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (6 g, 25.7 mmol)in DCM (50 mL) was added ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7.45 g,25.7 mmol), HATU (12.73 g, 33.5 mmol) and Et₃N (10.74 mL, 77 mmol). Thenthe mixture was stirred at 25° C. for 12 h. The mixture was washed withbrine and saturated NaHCO₃ solution. The organic layer was dried overMgSO₄, filtered and concentrated to yield a yellow oil of ethyl3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(12 g, 19.99 mmol, 78.0% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.94 (d,J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.36-7.25 (m, 3H), 7.22 (d, J=8.4Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.73 (s, 2H), 3.07 (s, 2H), 1.22 (t,J=7.2 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M).

Step 2: Ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

To a mixture of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(4.58 g, 11.90 mmol) and ethyl3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(6 g, 11.90 mmol) in H₂O (1 mL) and 1,4-dioxane (3 mL) was added Cs₂CO₃(7.75 g, 23.79 mmol) and PdCl₂(dppf) (0.435 g, 0.595 mmol) under N₂.Then the mixture was stirred and irradiated in a microwave oven at 120°C. for 30 min. The mixture was concentrated and extracted with EA. Thecombined organic layers were concentrated. The crude material waspurified by silica column chromatography (PE/EA=5:1). All fractionsfound to contain product by TLC (PE/EA=2:1, R_(f)=0.45) were combinedand concentrated to yield a yellow solid of ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(4.5 g, 4.63 mmol, 38.9% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.98-7.93(m, 2H), 7.70 (d, J=6.8 Hz, 1H), 7.46-7.35 (m, 6H), 7.23 (d, J=8.6 Hz,1H), 6.90 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.18-4.10 (m, 4H), 3.83-3.75(m, 5H), 3.09-3.05 (m, 2H), 1.41 (t, J=7.2 Hz, 3H), 1.24 (d, J=1.8 Hz,9H); ES-LCMS m/z 563 (M-120).

Step 3:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

To a mixture of ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate(3.5 g, 5.13 mmol) in THF (200 mL) cooled to 0° C. was added LAH (0.389g, 10.25 mmol) in portions. The mixture was stirred at 0° C. for 30 min.The mixture was quenched with 15% aqueous NaOH (10 mL). The mixture wasdried over Na₂SO₄. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica column chromatography(PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=2:1,R_(f)=0.35) were combined and concentrated to yield a light yellow oilof2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(3 g, 4.21 mmol, 82.0% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.93 (d, J=2.0Hz, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.47-7.31 (m, 7H), 6.90 (d, J=8.4 Hz,2H), 5.35 (s, 2H), 4.17-4.10 (m, 2H), 3.82-3.74 (m, 5H), 3.31-3.30 (m,2H), 2.77 (s, 2H), 1.41 (t, J=6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 635(M-120).

Step 4:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A mixture ofN-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(3 g, 3.97 mmol) and HCl (4 M in 1,4-dioxane, 20 mL) was stirred at 25°C. for 2 h. The mixture was concentrated. The crude material waspurified by preparative HPLC (MeCN/H₂O as eluants, acidic condition)twice to give a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(1528.59 mg, 2.94 mmol, 73.9% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.94(d, J=2.0 Hz, 1H), 7.74-7.67 (m, 1H), 7.44-7.38 (m, 2H), 7.37-7.27 (m,3H), 7.22 (d, J=2.0 Hz, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 2H),3.32-3.30 (m, 2H), 2.77 (s, 2H), 1.45 (t, J=6.8 Hz, 3H), 0.82 (s, 6H);ES-LCMS m/z 521 (M+1).

Example 62-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-3-fluorophenyl)methanol

To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) andNaBH₄ (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 mL) dropwiseat 20° C. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo. The residue was dissolvedin DCM (200 mL) and washed with H₂O (60 mL) and brine (60 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to yielda white solid of (4-bromo-3-fluorophenyl)methanol (9.8 g, 47.7 mmol,97.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.54 (t, J=7.8 Hz, 1H), 7.18 (d,J=9.6 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9(M-17).

Step 2: 1-Bromo-4-(bromomethyl)-2-fluorobenzene

To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) inDCM (100 mL) was added PBr₃ (2.76 mL, 29.3 mmol) dropwise. The resultingmixture was stirred at 20° C. After LCMS analysis showed the startingmaterial had disappeared, the mixture was adjusted to pH=8 by aqueousNa₂CO₃. The organic layer was dried and concentrated to give the crudeproduct, which was purified by column chromatography (PE/EA=10/1) toyield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g,14.89 mmol, 61.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J=7.6 Hz,1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H);ES-LCMS m/z 186.9 (M-79).

Step 3: 2-(4-Bromo-3-fluorophenyl)acetonitrile

To a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (1 g, 3.73mmol) in EtOH (30 mL) was added KCN (0.243 g, 3.73 mmol). The resultingmixture was stirred at 60° C. After 3 h, LCMS analysis showed thestarting material had disappeared. The solvent was removed in vacuo. Theresidue was dissolved in EA (80 mL) was washed with H₂O (30 mL) andbrine (30 mL). The organic layer was dried and concentrated to give thecrude product, which was purified by silica column chromatography(PE/EA=10/1) to yield a white solid of2-(4-bromo-3-fluorophenyl)acetonitrile (0.78 g, 2.96 mmol, 79.0% yield):¹H NMR (400 MHz, CD₃OD) δ 7.63 (t, J=7.8 Hz, 1H), 7.24 (d, J=9.2 Hz,1H), 7.12 (d, J=9.6 Hz, 1H), 3.92 (s, 2H); ES-LCMS m/z 214.0 (M+H).

Step 4: 2-(4-Bromo-3-fluorophenyl)acetic acid

A solution of 2-(4-bromo-3-fluorophenyl)acetonitrile (0.78 g, 3.64 mmol)in H₂SO₄ (5 mL) and

H₂O (5 mL) was stirred at 100° C. for 16 h. After LCMS analysis showedthe starting material had disappeared, the mixture was dissolved in H₂O(20 mL) and extracted by EA (20 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated to yield a white solid of2-(4-bromo-3-fluorophenyl)acetic acid (0.7 g, 2.046 mmol, 56.1% yield):¹H NMR (400 MHz, CD₃OD) δ 7.53 (t, J=7.8 Hz, 1H), 7.16 (dd, J=9.8, 1.9Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.61 (s, 2H).

Step 5:2-(4-Bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol),4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (78 mg,0.215 mmol), DIEA (83 mg, 0.644 mmol), HOBt (49.3 mg, 0.322 mmol) andEDC hydrochloride (61.7 mg, 0.322 mmol) in DCM (20 mL) was stirred at20° C. for 16 h. The mixture was washed with H₂O (20 mL) and brine (20mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude material was purified by preparative TLC (PE/EA=3/1) to yield2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(80 mg, 0.132 mmol, 61.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83 (d,J=2.0 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 7.15 (dd, J=9.7, 1.8 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H),3.62 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 0.86 (s, 9H), 0.76-0.69 (m,6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).

Step 6:N-(4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide

A solution of2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(80 mg, 0.139 mmol),3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(53.5 mg, 0.139 mmol), Cs₂CO₃ (90 mg, 0.278 mmol), PdCl₂(dppf) (10.15mg, 0.014 mmol) in 1,4-dioxane (9 mL) and H₂O (3 mL) was stirred at 110°C. for 15 min. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo. The residue was dissolvedin EA (60 mL) and washed with H₂O (20 mL) and brine (20 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by preparative TLC (PE/EA=2/1) to yieldN-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide(100 mg, 0.111 mmol, 80.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.84 (d,J=2.0 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.34-7.30 (m, 5H),7.17-7.15 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.27 (s, 2H), 4.04-3.99 (m,4H), 3.70 (s, 3H), 3.66 (s, 2H), 3.24 (s, 2H), 2.69 (s, 2H), 1.31 (t,J=7.0 Hz, 3H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z755.2 (M+H).

Step 7:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A solution ofN-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide(100 mg, 0.132 mmol) in HCl (MeOH, 5 mL, 20.00 mmol) was stirred at 20°C. After LCMS analysis showed the starting material had disappeared, thesolvent was removed in vacuo. The crude product was purified bypreparative HPLC to yield a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(37.98 mg, 0.073 mmol, 55.1% yield): ¹H NMR (400 MHz, CD₃OD) 7.94 (d,J=2.2 Hz, 1H), 7.70 (dd, J=2.0, 8.4 Hz, 1H), 7.51-7.45 (m, 1H),7.45-7.37 (m, 3H), 7.28-7.21 (m, 2H), 4.15 (m, 2H), 3.75 (s, 2H), 3.29(broad s, 2H), 2.77 (s, 2H), 1.46 (t, J=6.9 Hz, 3H), 0.82 (s, 6H);ES-LCMS m/z 521.2 (M+H).

Example 7N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide

Step 1: 2-(4-Bromo-3-fluorophenyl)acetate

To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (500 mg, 2.146mmol) in MeOH (10 mL, 247 mmol) was added sulfurous dichloride (0.232mL, 3.22 mmol). The resulting mixture was stirred at 60° C. After 3 h,LCMS analysis showed the starting material had disappeared and thesolvent was removed in vacuo. The residue was dissolved in DCM (60 mL)and washed with aqueous NaHCO₃ (20 mL) and brine (20 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated to yield a yellowoil of methyl 2-(4-bromo-3-fluorophenyl)acetate (500 mg, 1.774 mmol,83.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.53 (t, J=8.0 Hz, 1H), 7.15(dd, J=9.8, 1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 3.75-3.61 (m, 5H);ES-LCMS m/z 248.9 (M+H).

Step 2: Methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

A solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (0.5 g, 2.024mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.617 g, 2.429 mmol), PdCl₂(dppf) (0.148 g, 0.202 mmol) and KOAc (0.397g, 4.05 mmol) in 1,4-dioxane (5 mL) was stirred at 80° C. for 16 h.After LCMS analysis showed the starting material had disappeared, thesolvent was removed in vacuo. The residue was dissolved in EA (60 mL)and filtered. The filtrate was washed H₂O (20 mL) and brine (20 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography (PE/EA=5/1) to yielda yellow oil of methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(440 mg, 1.294 mmol, 63.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.62 (t,J=7.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.98 (d, J=10.4 Hz, 1H), 3.67 (s,5H), 1.33 (s, 12H); ES-LCMS m/z 295.1 (M+H).

Step 3:2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A solution of methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(0.1 g, 0.340 mmol) in ammonia (MeOH, 10 mL, 160 mmol) was stirred at20° C. for 16 h. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo to yield2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(100 mg, 0.286 mmol, 84.0% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (t,J=7.2 Hz, 1H), 7.14-6.98 (m, 2H), 3.59 (s, 2H), 1.26 (s, 12H); ES-LCMSm/z 280.1 (M+H).

Step 4:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide

A solution of2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(100 mg, 0.358 mmol), 2-(benzyloxy)-4-ethoxy-5-iodopyridine (127 mg,0.358 mmol), PdCl₂(dppf) (26.2 mg, 0.036 mmol) and Cs₂CO₃ (233 mg, 0.717mmol) in 1,4-dioxane (6 mL) and H₂O (2 mL) was stirred at 110° C. for 15min. After LCMS analysis showed the starting material had disappeared,the solvent was removed in vacuo. The residue was dissolved in EA (40mL) and washed with H₂O (20 mL) and brine (20 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product waspurified by preparative TLC (PE/EA=1/1) to yield2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20mg, 0.358 mmol, 14.8% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.87 (s, 1H),7.56-7.43 (m, 2H), 7.43-7.22 (m, 4H), 7.21-7.11 (m, 2H), 6.50 (s, 1H),5.38 (s, 2H), 4.13 (m, 2H), 3.58 (s, 2H), 1.32 (t, J=6.8 Hz, 3H);ES-LCMS m/z 381.1 (M+H).

Step 5:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide

A solution of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20mg, 0.053 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (13.14 mg,0.053 mmol), Pd₂(dba)₃ (4.81 mg, 5.26 μmol), Xantphos (3.04 mg, 5.26μmol) and Cs₂CO₃ (34.3 mg, 0.105 mmol) in 1,4-dioxane (2 mL) was stirredat 120° C. for 1 h. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo. The residue was dissolvedin EA (20 mL) and washed with H₂O (10 mL) and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by preparative TLC (PE/EA=2/1) to yield2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide(12 mg, 0.015 mmol, 28.5% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s,1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.84 (s, 1H),7.59-7.48 (m, 1H), 7.43-7.28 (m, 5H), 7.23-7.15 (m, 2H), 6.46 (s, 1H),5.34 (s, 2H), 4.09 (m, 2H), 3.73 (s, 3H), 1.28 (t, J=6.4 Hz, 3H);ES-LCMS m/z 550.1 (M+H).

Step 6:N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide

A solution of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide(12 mg, 0.022 mmol) and Pd/C (2.324 mg, 0.022 mmol) in MeOH (10 mL) wasstirred at 20° C. under a H₂ atmosphere for 16 h. After LCMS analysisshowed the starting material had disappeared, the mixture was filtered.The filtrate was concentrated to give the crude product, which waspurified by preparative HPLC to yield a white solid ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide(3.63 mg, 7.90 μmol, 36.2% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.23 (s,1H), 8.02-7.95 (m, 1H), 7.94-7.88 (m, 1H), 7.59 (s, 1H), 7.35-7.29 (m,1H), 7.25-7.15 (m, 2H), 6.23 (s, 1H), 4.16 (m, 2H), 3.80 (s, 2H), 1.32(t, J=7.0 Hz, 3H); ES-LCMS m/z 460.1 (M+H).

Example 82-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,6-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-2,6-difluorophenyl)methanol

To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) inTHF (100 mL) was added BH₃.DMS (20.03 mL, 211 mmol) dropwise at rt. Theresulting mixture was stirred at 60° C. for 16 h. After LCMS analysisshowed the starting material had disappeared, the mixture was quenchedby MeOH. The solvent was removed in vacuo to yield a white solid of(4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield),which was used in the next step without further purification: ES-LCMSm/z 222.1 (M+1).

Step 2: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene

To a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8.97 mmol)in DCM (80 mL) was added tribromophosphine (2.91 g, 10.76 mmol) at 0° C.The resulting mixture was stirred at rt. After LCMS analysis showed thestarting material had disappeared, the mixture was washed with aqueousNaHCO₃ (40 mL) and brine (30 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated. The crude material was purified bysilica column chromatography (PE/EA=5/1) to yield a colorless oil of5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.12 (d, J=6.8 Hz, 2H), 4.47 (s, 2H).

Step 3: 2-(4-Bromo-2,6-difluorophenyl)acetonitrile

To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g,5.60 mmol) in DMF (20 mL) was added KCN (0.401 g, 6.16 mmol). Theresulting mixture was stirred at 25° C. for 16 h. The mixture wasdissolved in H₂O (50 mL) and extracted by EA (50 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The crude material waspurified by silica column chromatography (PE/EA=3/1) to yield a whitesolid of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1.1 g, 2.57 mmol,45.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.36 (m, 2H), 3.89 (s, 2H).

Step 4: 2-(4-Bromo-2,6-difluorophenyl)acetic acid

A solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (0.5 g, 2.155mmol) in H₂SO₄ (3 mL, 56.3 mmol) and H₂O (3 mL, 167 mmol) was stirred at60° C. for 16 h. After LCMS analysis showed the starting material haddisappeared, the mixture was dissolved in H₂O (20 mL) and extracted byEA (2×30 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by silica columnchromatography (PE/EA=3/1 to 1/1) to yield2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 0.718 mmol, 33.3%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.13-7.05 (m, 2H), 3.71 (s, 2H).

Step 5:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide

To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL,0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMSanalysis showed the starting material had disappeared and the solventwas removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl)acetylchloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol)and Et₃N (0.225 g, 2.227 mmol) in DCM (30 mL) was added2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). Theresulting mixture was stirred at 25° C. After LCMS analysis showed thestarting material had disappeared, the mixture was washed with H₂O (20mL) and brine (20 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated, and purified by preparative TLC (PE/EA=3/1) togiveN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide(110 mg, 0.196 mmol, 17.6% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.81 (d,J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H),3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).

Step 6:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide

A solution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(78 mg, 0.202 mmol),N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide(110 mg, 0.202 mmol), PdCl₂(dppf)-DCM adduct (16.50 mg, 0.020 mmol) andCs₂CO₃ (132 mg, 0.404 mmol) in 1,4-dioxane (6 mL) and H₂O (2 mL) wasstirred at 110° C. for 15 min. After LCMS analysis showed the startingmaterial had disappeared, the solvent was removed in vacuo. The residuewas dissolved in DCM (60 mL) and washed with H₂O (20 mL) and brine (20mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude product was purified by preparative TLC (DCM/MeOH=10/1) toyieldN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.071 mmol, 35.1%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J=2.0 Hz, 1H), 7.84 (s, 1H),7.71 (d, J=11.2 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H),7.37-7.13 (m, 8H), 6.90 (d, J=8.6 Hz, 2H), 5.39-5.34 (m, 2H), 4.61 (s,2H), 4.27-4.20 (m, 2H), 4.18-4.10 (m, 2H), 3.86-3.82 (m, 2H), 3.78 (s,3H), 1.42 (t, J=6.9 Hz, 3H), 1.19 (s, 2H); ES-LCMS m/z 723.2 (M+H).

Step 7:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,6-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

A solution ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide(70 mg, 0.097 mmol) and Pd/C (10.31 mg, 0.097 mmol) in MeOH (10 mL) wasstirred under a H₂ atmosphere for 16 h. After LCMS analysis showed thestarting material had disappeared, the mixture was filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby preparative HPLC to yield a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,6-difluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide(7 mg, 0.014 mmol, 14.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83 (d,J=2.4 Hz, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.24 (dd,J=3.0, 5.4 Hz, 3H), 7.16 (d, J=9.0 Hz, 1H), 4.07-4.20 (m, 4H), 3.87 (t,J=5.0 Hz, 2H), 3.81 (s, 2H), 1.46 (t, J=7.06 Hz, 3H); ES-LCMS m/z 513.1(M+H).

Example 9N-(4-Cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydro-pyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 2-(4-Bromo-2-fluorophenyl)acetamide

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL,0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLCanalysis (PE/EA=1/1) showed the starting material had disappeared. Thesolvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetylchloride (110 mg, 0.416 mmol, 97% yield). A solution of2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resultingmixture was stirred at 0° C. After LCMS analysis showed the startingmaterial had disappeared, the solvent was removed in vacuo. The residuewas dissolved in EA (50 mL) and washed with H₂O (10 mL) and brine (10mL). The organic layer was dried and concentrated to give a white solidof 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9%yield), which was used into the next step without further purification:¹H NMR (400 MHz, CD₃OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H),3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).

Step 2:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

A solution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(133 mg, 0.345 mmol), 2-(4-bromo-2-fluorophenyl)acetamide (80 mg, 0.345mmol), Cs₂CO₃ (225 mg, 0.690 mmol) and PdCl₂(dppf) (25.2 mg, 0.034 mmol)in 1,4-dioxane (9 mL) and H₂O (3 mL) was stirred at 110° C. for 15 min.After LCMS analysis showed the starting material had disappeared, themixture was dissolved in H₂O (20 mL) and extracted by EA (50 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by preparative TLC (PE/EA=3/1) to yield ayellow solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(90 mg, 0.219 mmol, 63.6% yield): ¹H NMR (400 MHz, CD₃OD) 7.93 (d, J=2.0Hz, 1H), 7.43-7.34 (m, 6H), 6.91-6.89 (m, 2H), 5.35 (s, 2H), 4.16-4.11(m, 2H), 3.78 (s, 3H), 1.41 (t, J=7.0 Hz, 3H); ES-LCMS m/z 291.1(M-120).

Step 3:N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

A solution of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(10 mg, 0.024 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (6.09 mg,0.024 mmol), Pd₂(dba)₃ (2.231 mg, 2.436 μmol), Xantphos (1.410 mg, 2.436μmol) and Cs₂CO₃ (15.88 mg, 0.049 mmol) in 1,4-dioxane (1 mL) wasstirred at 120° C. for 1 h. After LCMS analysis showed the startingmaterial had disappeared, the solvent was removed in vacuo. The residuewas dissolved in EA (20 mL) and washed with H₂O (10 mL) and brine (10mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude material was purified by preparative TLC (PE/EA=1/1) to yielda white solid ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(15 mg, 0.013 mmol, 51.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.23 (s,1H), 7.98 (m, 1H), 7.94-7.90 (m, 2H), 7.44-7.37 (m, 6H), 6.90 (d, J=8.4Hz, 2H), 5.32 (s, 2H), 4.16-4.11 (m, 2H), 2.85 (s, 2H), 3.77 (s, 3H),1.41 (t, J=7.2 Hz, 3H); ES-LCMS m/z 460.1 (M-120).

Step 4:N-(4-Cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydro-pyridin-3-yl)-2-fluorophenyl)acetamide

A solution ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.026 mmol) in HCl(MeOH (solvate), 5 mL, 0.026 mmol) was stirred at 20° C. After LCMSanalysis showed the starting material had disappeared, the solvent wasremoved in vacuo. The crude product was purified by preparative HPLC toyield a white solid ofN-(4-cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(3 mg, 6.39 μmol, 24.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H),7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.41 (m, 1H), 7.37-7.34 (m, 3H),7.29 (d, J=2.0 Hz, 1H), 4.17-4.11 (m, 2H), 3.84 (s, 2H), 1.46 (t, J=6.8Hz, 3H); ES-LCMS m/z 460.1 (M+H).

Example 10N-(6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidedihydrochloride

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (5 g, 30.7mmol) in H₂SO₄ (30 mL, 563 mmol) was added nitric acid (1.507 mL, 33.7mmol) dropwise. After 30 min, the ice bath was removed and the reactionmixture was stirred at 25° C. for 16 h. The reaction mixture was warmedto 60° C. for 5 h, cooled, and added to 150 g of ice. The resultingprecipitate was collected by filtration, rinsed with additional H₂O, andair-dried to afford the first batch of product. Another crop of productwas obtained after evaporating the mother liquor to less than 100 mL,cooling on an ice bath, and adding NaOH to adjust to pH 8. The mixturewas extracted by EA (100 mL). The organic layer was dried andconcentrated to give the product, which was combined with the firstbatch to yield a yellow solid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol(5 g, 24.03 mmol, 78.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.85 (d, J=3.2Hz, 1H), 8.58 (d, J=2.8 Hz, 1H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (1 g, 4.81mmol) in SOCl₂ (10 mL, 137 mmol) was added DMF (0.372 mL, 4.81 mmol).The resulting mixture was stirred at 80° C. for 16 h. After TLC analysisshowed the starting material had disappeared, the solvent was removed invacuo. The residue was dissolved in DCM (60 mL) and washed with aqueousNaHCO₃ (20 mL) and brine (20 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (PE/EA=20/1) to yield a yellow solid of2-chloro-5-nitro-3-(trifluoromethyl)pyridine (0.8 g, 3.53 mmol, 73.5%yield): ¹H NMR (400 MHz, CD₃OD) δ 9.42 (d, J=2.8 Hz, 1H), 8.91 (d, J=2.4Hz, 1H).

Step 3:N,N-Dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine

To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (0.5,2.207 mmol) and 2-(dimethylamino)ethanol (0.393 g, 4.41 mmol) in THF (10mL) was added NaH (0.177 g, 4.41 mmol) at 0° C. The resulting mixturewas stirred at rt. After 5 h, TLC analysis showed the starting materialhad disappeared. The solvent was removed in vacuo. The residue wasdissolved in DCM (60 mL) and washed with H₂O (20 mL) and brine (20 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by silica column chromatography(DCM/MeOH=20/1) to yield a white solid ofN,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine(0.5 g, 1.717 mmol, 78.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.25 (d,J=2.4 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 4.73 (t, J=5.4 Hz, 2H), 2.88 (t,J=5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H).

Step 4: 6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine

A solution ofN,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-ypoxy)ethanamine(500 mg, 1.791 mmol) and Pd/C (191 mg, 1.791 mmol) in MeOH (30 mL) wasstirred at 20° C. under H₂. After TLC analysis (DCM/MeOH=20/1) showedthe starting material had disappeared, the mixture was filtered. Thefiltrate was concentrated to yield a oil of6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (360 mg,1.444 mmol, 81.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.77 (d, J=2.4 Hz,1H), 7.37 (d, J=3.2 Hz, 1H), 4.43 (t, J=5.6 Hz, 2H), 2.78 (t, J=6.4 Hz,2H), 2.35 (s, 6H); ES-LCMS m/z 250.1 (M+H).

Step 5:2-(4-Bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429mmol), 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine(107 mg, 0.429 mmol) and HATU (245 mg, 0.644 mmol) in DCM (15 mL) wasadded DIEA (0.225 mL, 1.287 mmol). The resulting mixture was stirred at20° C. for 16 h. The mixture was washed with H₂O (20 mL) and brine (20mL). The organic layer was dried over Na₂SO₄, filtered and concentrated.The crude product was purified by preparative TLC (DCM/MeOH=10/1) toyield a brown oil of2-(4-bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide(130 mg, 0.273 mmol, 63.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d,J=2.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.38-7.26 (m, 4H), 4.62 (t, J=5.4Hz, 2H), 3.75 (s, 2H), 3.08 (t, J=5.2 Hz, 2H), 2.56 (s, 6H); ES-LCMS m/z464.0 (M+H).

Step 6:N-(6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A solution of2-(4-bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (0.1 g, 0.215 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.066 g,0.258 mmol), PdCl₂(dppf) (0.016 g, 0.022 mmol) and KOAc (0.042 g, 0.431mmol) in 1,4-dioxane (5 mL) was stirred at 80° C. for 16 h. After LCMSanalysis showed the starting material had disappeared, the solvent wasremoved in vacuo. The residue was purified by preparative TLC(DCM/MeOH=20/1) to yieldN-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(42 mg, 0.076 mmol, 35.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s,1H), 8.30 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.43-7.30 (m, 2H), 4.75-4.68(m, 2H), 3.80 (s, 2H), 3.41 (s, 2H), 2.82 (s, 6H), 1.33 (s, 12H);ES-LCMS m/z 512.2 (M+H).

Step 7:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide

A solution ofN-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(30 mg, 0.059 mmol), 2-(benzyloxy)-4-ethoxy-5-iodopyridine (20.84 mg,0.059 mmol), PdCl₂(dppf) (42.9 mg, 0.059 mmol) and Cs₂CO₃ (19.12 mg,0.059 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) was stirred at 110° C.for 15 min. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo. The residue was dissolvedin EA (30 mL) and washed with H₂O (10 mL) and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by preparative TLC (DCM/MeOH=10/1) to yield2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide(5 mg, 6.97 μmol, 11.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H),8.33 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.48-7.30 (m, 8H), 6.51 (s, 1H),5.38 (s, 2H), 4.64 (t, J=5.2 Hz, 2H), 4.16 (m, 2H), 3.84 (s, 2H), 3.03(t, J=5.2 Hz, 2H), 2.53 (s, 6H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z613.1 (M+H).

Step 8:N-(6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidedihydrochloride

A solution of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (5 mg, 8.16μmol) and Pd/C (0.869 mg, 8.16 μmol) in MeOH (10 mL) was stirred at 20°C. under H₂ (0.016 mg, 8.16 μmol) for 16 h. After LCMS analysis showedthe starting material was consumed, the mixture was filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby preparative HPLC to give a colorless oil ofN-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidedihydrochloride (1 mg, 1.680 μmol, 20.6% yield): ¹H NMR (400 MHz, CD₃OD)δ 8.63 (s, 1H), 8.37 (s, 1H), 7.62 (d, J=6.4 Hz, 1H), 7.46-7.42 (m, 1H),7.31-7.28 (m, 2H), 6.21 (d, J=11.8 Hz, 1H), 4.23-4.18 (m, 2H), 3.86 (s,2H), 3.69-3.67 (m, 2H), 3.33 (m, 2H), 3.04 (s, 6H), 1.42 (t, J=7.0 Hz,3H); ES-LCMS m/z 523.2 (M+H).

Example 112-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

A suspension of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline(6.63 mg, 0.027 mmol) in DMF (5 mL) was added to a solution of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(8 mg, 0.027 mmol) in DMF (5 mL). HOBt (6.31 mg, 0.041 mmol), EDC (7.90mg, 0.041 mmol) and Et₃N (0.011 mL, 0.082 mmol) were added and themixture was stirred at 50° C. for 12 h. Then the solution wasconcentrated and distributed between EA and saturated NaHCO₃ solution.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative HPLC (MeCN/H₂O as eluants, acidic condition) to yield an offwhite solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride (1.60 mg, 2.90 μmol, 10.6% yield). TLC (DCM/MeOH=10:1,R_(f)=0.3): ¹H NMR (400 MHz, CD3OD) δ: 9.41 (d, J=1.54 Hz, 1H),8.37-8.45 (m, 1H), 7.96 (s, 1H), 7.73-7.88 (m, 2H), 7.18-7.52 (m, 5H),4.14 (q, J=7.06 Hz, 2H), 3.87 (s, 2H), 2.43 (s, 3H), 1.46 (t, J=6.95 Hz,3H); ES-LCMS m/z 515.1 (M+H).

Example 12N-(6-(2-Cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1:2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

K₂CO₃ (359 mg, 2.60 mmol) was added to a solution of2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (200 mg, 0.865mmol) in MeCN (10 mL). MeI (3071 mg, 21.63 mmol) was added and themixture was at 40° C. for 10 h. Then the solution was concentrated anddistributed between EA and saturated NaHCO₃ solution. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by preparative TLC(PE/EA=5:1, R_(f)=0.5) to yield a light yellow solid of2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (129mg, 0.498 mmol, 57.5% yield): ¹H NMR (400 MHz, CDCl₃) δ: 9.54 (d, J=2.2Hz, 1H), 8.65-9.07 (m, 1H), 1.92 (s, 6H); ES-LCMS m/z 260.1 (M+H).

Step 2:2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile

Tin(II) chloride dihydrate (449 mg, 1.991 mmol) was added to a solutionof 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile(129 mg, 0.498 mmol) in EA (15 mL). The mixture was at 60° C. for 4 h.Then the solution was adjusted to pH=8-9 with 2N NaOH. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by preparative HPLC(MeCN/H₂O as eluants, basic condition) to yield a white solid of2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile(46.48 mg, 0.203 mmol, 40.7% yield). TLC (PE/EA=1:1, R_(f)=0.3): ¹H NMR(400 MHz, DMSO-d₆) δ 8.04-8.17 (m, 1H), 7.31 (d, J=2.43 Hz, 1H), 5.97(s, 2H), 1.70 (s, 6H); ES-LCMS m/z 230.1 (M+H).

Step 3:N-(6-(2-Cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

A suspension of2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile(13.91 mg, 0.061 mmol) in DMF (5 mL) was added to a solution of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(52 mg, 0.061 mmol) in DMF (5 mL). HOBt (13.94 mg, 0.091 mmol), EDC(17.45 mg, 0.091 mmol) and Et₃N (0.025 mL, 0.182 mmol) and the mixturewas at 50° C. for 12 h. Then the solution was concentrated anddistributed between EA and saturated NaHCO₃ solution. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by preparative HPLC(MeCN/H₂O as eluants, acidic condition) to yield an off white solid ofN-(6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (8.62 mg, 0.016 mmol, 26.4% yield). TLC (DCM/MeOH=10:1,R_(f)=0.3): ¹H NMR (400 MHz, CD₃OD) δ: 8.95 (d, J=2.2 Hz, 1H), 8.56 (d,J=2.4 Hz, 1H), 7.26-7.47 (m, 5H), 4.14 (q, J=7.0 Hz, 2H), 3.81-3.90 (m,2H), 1.77-1.91 (m, 6H), 1.47 (t, J=6.9 Hz, 3H); ES-LCMS m/z 503.1 (M+H).

Example 132-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide

A suspension of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (668mg, 2.146 mmol) in DCM (35 mL) was added to a solution of2-(4-bromo-2-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in DCM (35mL). HOBt (493 mg, 3.22 mmol), EDC (617 mg, 3.22 mmol) and Et₃N (0.897mL, 6.44 mmol) and the mixture was at 26° C. for 3 h. Then the solutionwas concentrated and distributed between EA and saturated NaHCO₃solution. The combined organic extract was washed with brine, dried overMgSO₄, filtered and concentrated. The crude material was purified bysilica column chromatography (PE/EA=10/1). All fractions found tocontain product by TLC (PE/EA=5/1, R_(f) 0.6) were combined andconcentrated to yield a light yellow solid ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide(1 g, 1.900 mmol, 89.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83-7.82 (d,J=2.8 Hz, 1H), 7.33-7.24 (m, 10H), 4.83 (s, 1H), 4.23-4.21 (m, 2H),3.84-3.83 (m, 2H), 3.71-3.67 (m, 2H); ES-LCMS m/z 525.9 (M+H).

Step 2:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

A suspension ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide(800 mg, 1.520 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) was added to asolution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(586 mg, 1.520 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL). PdCl₂(dppf)(111 mg, 0.152 mmol) and Cs₂CO₃ (990 mg, 3.04 mmol) were added and themixture was at 110° C. for 30 min under microwave. The mixture wascooled to rt. Then the solution was concentrated and distributed betweenEA and saturated NaHCO₃ solution. The combined organic extract waswashed with brine, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by preparative TLC (PE/EA=1/1, R_(f)=0.5) toyield a light yellow solid ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(230 mg, 0.326 mmol, 21.5% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.95-7.94(d, J=2.0 Hz, 1H), 7.90-7.89. (d, J=2.8 Hz, 1H), 7.45-7.38 (m, 6H),7.37-7.25 (m, 6H), 6.92-6.90 (m, 2H), 5.36 (s, 2H), 4.61 (s, 2H),4.25-4.24 (m, 2H), 4.23-4.11 (m, 2H), 3.85-3.83 (m, 2H), 3.79-3.77 (m,2H), 1.45-1.41 (t, J=4.8 Hz, 3H); ES-LCMS m/z 705.1 (M+H).

Step 3:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

A suspension ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(50 mg, 0.071 mmol) in MeOH (10 mL) was added to a solution of Pd/C(15.10 mg, 0.142 mmol) in MeOH (10 mL). The mixture was hydrogenatedunder a H₂ atmosphere at 26° C. for 2 h. Then the solution was filteredand concentrated. The crude material was purified by preparative HPLC(MeCN/H₂O as eluants, basic condition) to yield a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide(26.17 mg, 0.053 mmol, 74.6% yield). TLC (DCM/MeOH=10/1, R_(f)=0.4): ¹HNMR (400 MHz, CD₃OD) δ 7.84-7.83 (m, 1H), 7.72-7.70 (d, J=8.8 Hz, 1H),7.43-7.41 (m, 1H), 7.39-7.29 (m, 3H), 7.23-7.22 (d, J=2.0 Hz, 1H),7.17-7.15 (d, J=9.2 Hz, 1H), 4.14-4.11 (m, 4H), 3.88-3.86 (m, 2H), 3.76(s, 2H), 1.47-1.44 (t, J=7.0 Hz, 3H); ES-LCMS m/z 495.0 (M+H).

Example 14N-(6-(Cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

A suspension of tin(II) chloride dihydrate (58.6 mg, 0.260 mmol) in EA(60 mL) was added to a solution of2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (30 mg, 0.130mmol) in EA (60 mL). The mixture was at 50° C. for 3 h. Then thesolution was concentrated and distributed between EA and saturatedNaHCO₃ solution. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The resulting2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16 mg, 0.080mmol, 61.3% yield) was used in the next step without furtherpurification. TLC (PE/EA=1:1, R_(f)=0.5): ¹H NMR (400 MHz, CDCl₃) δ:8.19-8.27 (m, 1H), 7.22 (d, J=2.5 Hz, 1H), 3.97 (s, 2H); ES-LCMS m/z202.0 (M+H).

Step 2:N-(6-(Cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile(16.00 mg, 0.080 mmol) in DMF (5 mL) was added to a solution of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(46.33 mg, 0.080 mmol) in DMF (5 mL). HOBt (18.27 mg, 0.119 mmol), EDC(22.87 mg, 0.119 mmol) and Et₃N (0.033 mL, 0.239 mmol) and the mixturewas at 50° C. for 12 h. Then the solution was concentrated anddistributed between EA and saturated NaHCO₃ solution. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by preparative HPLC(MeCN/H₂O as eluants, acidic condition) to yield a yellow solid ofN-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (0.96 mg, 1.879 μmol, 2.4% yield). TLC (DCM/MeOH=10:1,R_(f)=0.3): ¹H NMR (400 MHz, CD₃OD) δ: 8.87-8.96 (m, 1H), 8.56 (d,J=2.21 Hz, 1H), 7.19-7.50 (m, 5H), 4.08-4.18 (m, 2H), 3.85 (s, 3H), 3.58(s, 2H), 1.29-1.35 (m, 3H); ES-LCMS m/z 475.0 (M+H).

Example 15N-(6-(1-Cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

K₂CO₃ (359 mg, 2.60 mmol) was added to a solution of2-(5-nitro-3-(trifluoromethyl)pyridine-2-yl)acetonitrile (200 mg, 0.865mmol) in MeCN (10 mL). MeI (3071 mg, 21.63 mmol) was added and themixture was stirred at 40° C. for 10 h. Then the solution wasconcentrated and distributed between EA and saturated NaHCO₃ solution.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative TLC (PE/EA=5:1, Rf=0.5) to yield a light yellow solid of2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg,0.300 mmol, 34.7% yield): ¹H NMR (400 MHz, CDCl₃) δ: 9.65 (d, J=2.2 Hz,1H), 9.54 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.2 Hz, 1H), 8.80 (d, J=2.0 Hz,1H), 4.47 (q, J=7.1 Hz, 1H), 1.92 (s, 2H), 1.78 (d, J=7.1 Hz, 3H);ES-LCMS m/z 246.0 (M+H).

Step 2: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

Tin(II) chloride dihydrate (135 mg, 0.600 mmol) was added to a solutionof 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg,0.300 mmol) in EA (15 mL). The mixture was at 50° C. for 3 h. Then thesolution was concentrated and distributed between EA and saturatedNaHCO₃ solution. The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The resulting2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55 mg, 0.256mmol, 85.0% yield) was used to next step without further purification.TLC (PE/EA=5:1, R_(f)=0.5): ¹H NMR (400 MHz, CDCl₃) δ: 8.25 (s, 1H),7.17 (d, J=2.2 Hz, 1H), 4.15-4.28 (m, 1H), 1.66 (d, J=7.1 Hz, 3H);ES-LCMS m/z 216.0 (M+H).

Step 3:N-(6-(1-Cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

A suspension of2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55.6 mg,0.258 mmol) in DMF (10 mL) was added to a solution of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(125.4 mg, 0.258 mmol) in DMF (10 mL). HATU (147 mg, 0.387 mmol) andDIEA (0.135 mL, 0.775 mmol) were added and the mixture was at 50° C. for12 h. Then the solution was concentrated and distributed between EA andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by preparative HPLC (MeCN/H₂O as eluants, acidic condition)to yield an off white solid of N-(6-(1-cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (10.59 mg, 0.020 mmol, 7.8% yield). TLC (DCM/MeOH=10:1,R_(f)=0.3): ¹H NMR (400 MHz, CD₃OD) δ: 8.96 (s, 1H), 8.49-8.65 (m, 1H),7.17-7.53 (m, 5H), 4.46 (q, J=7.0 Hz, 1H), 4.07-4.20 (m, 2H), 3.86 (s,2H), 1.67 (d, J=7.1 Hz, 3H), 1.37-1.53 (m, 3H); ES-LCMS m/z 489.1 (M+H).

Example 16N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

A suspension of 4-chloro-3-(trifluoromethyl)aniline (20.14 mg, 0.103mmol) in DMF (8 mL) was added to a solution of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(30 mg, 0.103 mmol) in DMF (8 mL). HOBt (23.66 mg, 0.154 mmol), EDC(29.6 mg, 0.154 mmol) and Et₃N (0.043 mL, 0.309 mmol) were added and themixture was stirred at 50° C. for 8 h. Then the solution wasconcentrated and distributed between EA and saturated NaHCO₃ solution.The combined organic extract was washed with brine, dried over MgSO₄,filtered and concentrated. The crude material was purified bypreparative HPLC (MeCN/H₂O as eluants, acidic condition) to yield awhite solid of N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(11.39 mg, 0.024 mmol, 23.6% yield). TLC (DCM/MeOH=10:1, R_(f)=0.6): ¹HNMR (400 MHz, CD₃OD) δ: 8.10 (s, 1H), 7.79 (d, J=8.82 Hz, 1H), 7.53 (d,J=8.82 Hz, 1H), 7.37-7.44 (m, 1H), 7.26-7.37 (m, 3H), 7.23 (d, J=1.98Hz, 1H), 4.12 (q, J=7.06 Hz, 2H), 3.80 (s, 2H), 1.46 (t, J=6.95 Hz, 3H);ES-LCMS m/z 469.1 (M+H).

Example 17N-(4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1: N,N-Dimethyl-4-nitro-2-(trifluoromethyl)benzamide

To a solution of 4-nitro-2-(trifluoromethyl)benzoic acid (10 g, 42.5mmol), dimethylamine (hydrochloride, 4.51 g, 55.3 mmol) and Et₃N (17.78mL, 128 mmol) in DCM (150 mL) stirred under nitrogen at 20° C. was addedHATU (19.41 g, 51.0 mmol) in one charge. The reaction mixture wasstirred at 20° C. for 2 h. Then the solution was distributed between DCMand saturated NaHCO₃ solution. The combined organic extract was washedwith brine, dried over MgSO₄, filtered and concentrated. The resultingN,N-dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10 g, 25.2 mmol,59.2% yield) was used in the next step without further purification. TLC(PE/EA=5:1, R_(f) 0.6): ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=1.8 Hz,1H), 8.46 (dd, J=2.0, 8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 2.79 (s, 6H);ES-LCMS m/z 263.0 (M+H).

Step 2: 4-Amino-N,N-dimethyl-2-(trifluoromethyl)benzamide

To a solution of N,N-dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10g, 25.2 mmol) in MeOH (100 mL) stirred under N₂ at 20° C. was added Pd/C(1 g, 9.40 mmol) in one charge. The reaction mixture stirred under a H₂atmosphere at 20° C. for 12 h. The mixture was filtered, and thefiltrate was concentrated in vacuo to give the desired product4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol,94.0% yield). TLC (DCM/MeOH=10:1, R_(f)=0.4): ¹H NMR (400 MHz, CDCl₃) δ7.07 (d, J=8.2 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8.2 Hz, 1H), 3.95 (br.s., 2H), 3.08 (s, 3H), 2.80 (s, 3H); ES-LCMS m/z 233.0 (M+H).

Step 3: 44(Dimethylamino)methyl)-3-(trifluoromethyl)aniline

To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3g, 23.59 mmol) in THF (100 mL) stirred under a N₂ atmosphere at 20° C.was added BH₃DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture wasstirred at 80° C. for 2 h. To the solution was added MeOH, thenconcentrated in vacuo to give the crude product. The crude material waspurified by silica column chromatography (DCM/MeOH=30:1). All fractionsfound to contain product by TLC (DCM/MeOH=10:1, R_(f)=0.4) were combinedand concentrated to yield light yellow oil of4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol,78.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s,1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2(M+H).

Step 4:2-(4-Bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide

To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)anilinedihydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid(3.20 g, 13.74 mmol) and Et₃N (9.57 mL, 68.7 mmol) in DCM (100 mL)stirred under a N₂ atmosphere at 20° C. were added EDC (2.63 g, 13.74mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixturewas stirred at 20° C. for 2 h. Then the solution was concentrated anddistributed between EA and saturated NaHCO₃ solution. The combinedorganic extract was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by silica columnchromatography (PE/EA=3:1). All fractions found to contain product byTLC (PE/EA=2:1, R_(f) 0.6) were combined and concentrated to yield alight yellow solid of2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide(5.5 g, 9.14 mmol, 66.5% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.79 (br. s.,2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s,2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H).

Step 5:N-(44(Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a solution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(3.52 g, 9.14 mmol),2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide(5.5 g, 9.14 mmol) and Cs₂CO₃ (7.45 g, 22.85 mmol) in 1,4-dioxane (30mL) and H₂O (10.00 mL) stirred under a N₂ atmosphere at 20° C. was addedPdCl₂(dppf) (0.334 g, 0.457 mmol) in one charge. The reaction vessel washeated in 110° C. for 3 h. Then the solution was concentrated anddistributed between EA and H₂O. The combined organic extract was washedwith brine, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by silica column chromatography (PE/EA=1:1). Allfractions found to contain product by TLC (PE/EA=1:1, R_(f) 0.3) werecombined and concentrated to yield a white solid ofN-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(5.8 g, 7.30 mmol, 80.0% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.98 (m,3H), 7.67 (d, J=8.6 Hz, 1H), 7.37-7.47 (m, 3H), 7.26-7.35 (m, 2H), 7.20(d, J=2.0 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 5.44 (s, 2H), 4.13 (q, J=7.0Hz, 2H), 3.75-3.86 (m, 5H), 3.70 (br. s., 2H), 2.35 (br. s., 6H), 1.46(t, J=7.0 Hz, 3H) ES-LCMS m/z 612.2 (M+H).

Step 6:N-(44(Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

To a solution ofN-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(5.8 g, 7.30 mmol) in DCM (50 mL) was added HCl (1,4-dioxane, 5 mL,20.00 mmol) at rt. The solution was stirred at 20° C. for 30 min. Thesolution was concentrated in vacuo to give the crude product. The crudematerial was purified by preparative HPLC (MeCN/H₂O as eluants, acidiccondition) to yield an off white solid ofN-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (1.5 g, 2.78 mmol, 38.1% yield). TLC (DCM/MeOH=5:1,R_(f)=0.3): ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J=1.4 Hz, 1H), 8.04 (d,J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.36-7.53 (m, 5H), 4.50 (s, 2H),4.20 (q, J=7.0 Hz, 2H), 3.87 (s, 2H), 2.95 (s, 6H), 1.50 (t, J=7.0 Hz,3H); ES-LCMS m/z 492.2 (M+H).

Example 18N-(3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 2-(4-Bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (144 mg, 0.617mmol), 3,4-dichloroaniline (100 mg, 0.617 mmol) and HATU (704 mg, 1.852mmol) in DCM (20 mL) was added Et₃N (0.258 mL, 1.852 mmol) dropwise.Then the mixture was stirred at 20° C. under a N₂ atmosphere for 3 h.After LCMS analysis showed the starting material had disappeared, thesolvent was removed in vacuo. Then the crude product was dissolved inDCM and washed with H₂O and brine. The organic layer was evaporated todryness to give the crude product which was purified by silica columnchromatography (PE/EA=100/1 to 8/1) to afford pure product2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (190 mg,0.419 mmol, 67.8% yield): ¹H NMR: (400 MHz, CD₃OD) δ 10.25 (br. s, 1H),7.89 (s, 1H), 7.44 (s, 2H), 7.28-7.37 (m, 3H), 3.74 (s, 2H); ES-LCMS:m/z 377.9 (M+H).

Step 2:N-(3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a solution of2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (60 mg, 0.159mmol),3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(61.3 mg, 0.159 mmol) and Cs₂CO₃ (156 mg, 0.477 mmol) in 1,4-dioxane (3mL) and H₂O (1 mL) was added PdCl₂(dppf) (11.64 mg, 0.016 mmol) in onecharge. The mixture was stirred at 130° C. in the microwave for 30 min.After LCMS analysis showed the starting material had disappeared, themixture was filtered. The filtrate was concentrated and evaporated todryness to give crude product which was dissolved in DCM and washed withH₂O and brine. Then the crude product was purified by preparative TLC(DCM/MeOH=40/1) to give pure productN-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(60.0 mg, 0.084 mmol, 52.7% yield): ¹H NMR: (400 MHz, CD₃OD) δ 7.95 (d,J=2.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.45 (s, 3H), 7.43-7.37 (m, 5H),6.91 (d, J=8.6 Hz, 2H), 5.37 (s, 2H), 4.15 (m, 3H), 3.79 (s, 4H), 1.42(t, J=7.0 Hz, 3H); ES-LCMS: m/z 435 (M-120).

Step 3:N-(3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

A solution ofN-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(60 mg, 0.108 mmol) in HCl (MeOH, 27.0 μl, 0.108 mmol) was stirred at20° C. for 1 h. After LCMS analysis showed the starting material haddisappeared, the solvent was removed in vacuo. The crude product waspurified by preparative HPLC to give pure productN-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(14.72 mg, 0.034 mmol, 31.3% yield): ¹H NMR: (400 MHz, CD₃OD) δ 7.92 (s,1H), 7.45 (s, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.38-7.32 (m, 3H), 7.28-7.25(m, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.14 (m, 2H), 3.79 (s, 2H), 1.47 (t,J=7.0 Hz, 3H); ES-LCMS: m/z 435.0 (M+H).

Example 192-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

Step 1:2-(4-Bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429mmol) in DCM (50 mL) was added5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (92 mg, 0.472mmol), HATU (245 mg, 0.644 mmol) and Et₃N (0.179 mL, 1.287 mmol). Thenthe mixture was stirred at 25° C. for 12 h. The mixture was concentratedand the crude material was purified by preparative TLC (PE/EA=2:1,Rf=0.4) to yield a yellow oil of2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(50 mg, 0.109 mmol, 25.4% yield): ¹H NMR (400 MHz, CDCl₃) δ: 8.12 (s.,1H) 7.35-7.27 (m, 2H) 7.23-7.18 (m, 1H) 6.95 (s, 1H) 3.72 (s, 2H) 1.55(s, 6H); ES-LCMS m/z 411 (M+2).

Step 2:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

To a mixture of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(60 mg, 0.156 mmol),2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(63.7 mg, 0.156 mmol) in H₂O (1 mL) and 1,4-dioxane (3 mL) was addedCs₂CO₃ (101 mg, 0.311 mmol) and PdCl₂(dppf) (11.40 mg, 0.016 mmol) undera N₂ atmosphere. Then the mixture was stirred and irradiated in amicrowave oven at 120° C. for 30 min. The mixture was concentrated andextracted with EA. The combined organic was concentrated and the crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.5) to givea yellow solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(20 mg, 0.031 mmol, 19.9% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.97 (d,J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.46-7.37 (m, 5H), 6.97-7.89 (m,3H), 5.39 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.85 (s, 2H), 3.83-3.79 (m,3H), 1.60 (s, 6H), 1.45 (t, J=7.0 Hz, 3H); ES-LCMS m/z 588 (M+1).

Step 3:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(20 mg, 0.034 mmol) and HCl (4 M in dioxane, 20 mL) was stirred at 25°C. for 2 h. The mixture was concentrated and the crude material waspurified by preparative HPLC (MeCN/H₂O as eluants, acidic condition) togive a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(7.9 mg, 0.017 mmol, 49.7% yield): ¹H NMR (400 MHz, CD₃OD) δ: 7.42-7.36(m, 1H), 7.35 (s, 2H), 7.29 (d, J=2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H),6.87 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.46(t, J=6.8 Hz, 3H); ES-LCMS m/z 468 (M+1).

Example 202-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide

A suspension of 2-(4-bromo-2-fluorophenyl)acetic acid (600 mg, 2.57mmol), EDC (592 mg, 3.09 mmol), HOBt (473 mg, 3.09 mmol), Et₃N (1.056mL, 7.72 mmol) in DCM (10 mL) was stirred for 2 h at rt. The mixture wasextracted with DCM (2×50 mL). The organic extract was washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by preparative TLC to yieldN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide(450 mg, 0.496 mmol, 19.3% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83-7.82(d, J=2.4 Hz, 1H), 7.71-7.68 (dd, J=8.8, 2.4 Hz, 1H), 7.34-7.29 (m, 1H),7.15-7.13 (d, J=8.8 Hz, 1H), 4.60 (s, 2H), 4.23 (t, J=4.8 Hz, 2H) 3.83(t, J=4.6 Hz, 2H), 3.71 (s, 2H); ES-LCMS m/z 526 (M+H).

Step 2:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A suspension ofN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide(300 mg, 0.570 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (145 mg,0.570 mmol), PdCl₂(dppf) (41.7 mg, 0.057 mmol), KOAc (112 mg, 1.140mmol) in 1,4-dioxane (10 mL) was heated to 100° C. for 120 min under aN₂ atmosphere. The mixture was concentrated to give the residue whichwas extracted with DCM (20 mL×2). Then the mixture was concentrated togive the residue which was extracted with DCM (20 mL×2). The organicextract was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by preparative TLC(EA/PE=1:1, Rf=0.5) to yieldN-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(300 mg, 0.314 mmol, 55.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.84 (d,J=2.6 Hz, 1H), 7.70 (dd, J=9.0, 2.4 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H),7.42-7.21 (m, 7H), 7.14 (d, J=9.0 Hz, 1H), 4.29-4.19 (m, 2H), 3.89-3.82(m, 2H), 3.76 (s, 2H), 1.33 (s, 12H); ES-LCMS m/z 721 (M+H).

Step 3:N-(4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-((5-ethoxy-6-((4-methoxybenzyl)oxypyridin-3-yl)oxy)-2-fluorophenyl)acetamide

A suspension of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (80 mg, 0.225mmol),N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(129 mg, 0.225 mmol), PdCl₂(dppf) (16.48 mg, 0.023 mmol), Cs₂CO₃ (73.4mg, 0.225 mmol) in 1,4-dioxane (5 mL) and H₂O (1 mL) was heated to 100°C. for 20 min under a N₂ atmosphere in a microwave. Then the mixture wasconcentrated to give the residue which was extracted with DCM (20 mL×2).The organic extract was washed with brine, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by preparative TLC(EA/PE=1:1, Rf=0.5) to yield2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide(60 mg, 0.054 mmol, 24.1% yield):

¹H NMR (400 MHz, CD₃OD) δ 7.95 (s., 1H), 7.85-7.84 (d, J=2.4 Hz, 1H),7.74-7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.44-7.42 (m, 2H), 7.38-7.24 (m,10H), 7.16-7.14 (d, J=8.8 Hz, 1H), 6.48 (s, 1H), 5.35 (s, 2H), 4.61 (s,2H), 4.23 (t, J=4.6 Hz, 2H), 4.15-4.10 (m, 3H), 3.84 (t, J=4.6 Hz, 2H),3.77 (s, 2H), 3.66-3.65 (m, 1H), 3.55-3.54 (m, 1H), 1.36 (t, J=7.2 Hz,3H); ES-LCMS m/z 721 (M+H).

Step 4:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

A mixture of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide(60 mg, 0.089 mmol), Pd/C (9.46 mg, 0.089 mmol) in MeOH (10 mL) wasstirred for 16 h under a H₂ atmosphere at 25° C. Then the mixture wasfiltered and the filtrate was concentrated to give the residue which waspurified by preparative HPLC to yield2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide(17.76 mg, 0.034 mmol, 38.8% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83 (d,J=2.4 Hz., 1H), 7.73-7.70 (m, 1H), 7.35-7.29 (m, 2H), 7.42 (s, 1H), 7.37(d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 7.17-7.14 (d, J=4.6 Hz, 1H), 6.03(s, 1H), 4.13-4.11 (m, 4H), 3.87 (t, J=5.0 Hz, 2H), 3.76 (s, 2H), 1.37(t, J=7.0 Hz, 3H); ES-LCMS m/z 495 (M+H).

Example 212-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide,dihydrochloride

Step 1:2-(4-Bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide

A suspension of4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg,0.858 mmol) in DCM (35 mL) was added to a solution of2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et₃N (0.359mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h.Then the solution was concentrated and distributed between EA andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by silica column chromatography (PE/EA=10/1). All fractionsfound to contain product by TLC (PE/EA=5/1, R_(f)=0.6) were combined andconcentrated to yield a light yellow solid of2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide(413 mg, 0.822 mmol, 96.0% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.98-7.91(m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s,2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H).

Step 2:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide

A suspension of2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide(413 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) was added to asolution of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(317 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL). PdCl₂(dppf)(60.2 mg, 0.082 mmol) and Cs₂CO₃ (536 mg, 1.644 mmol) were added and themixture was at 110° C. for 30 min in a microwave. The mixture was cooledto rt. Then the solution was concentrated and distributed between EA andsaturated NaHCO₃ solution. The combined organic extract was washed withbrine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by preparative TLC (PE/EA=1/1, R_(f)=0.5) to yield a lightyellow solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide(405 mg, 0.595 mmol, 72.4% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.02-7.87(m, 2H), 7.82-7.64 (m, 2H), 7.60-7.30 (m, 6H), 6.98-6.80 (m, 2H), 5.34(s, 2H), 4.18-4.04 (m, 2H), 3.84-3.72 (m, 4H), 3.68-3.57 (m, 2H),2.91-2.38 (m, 10H), 1.47-1.31 (m, 3H), 1.14 (s, 3H); ES-LCMS m/z 681.3(M+H).

Step 3:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamidedihydrochloride

A suspension of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide(400 mg, 0.588 mmol) in MeOH (10 mL) was added to a solution of Pd/C(62.5 mg, 0.588 mmol) in MeOH (10 mL). The mixture was hydrogenated at26° C. for 2 h. Then the solution was filtered and concentrated. Thecrude material was purified by preparative HPLC (MeCN/H₂O as eluants,acidic condition) to yield a light yellow solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide,dihydrochloride (40.71 mg, 0.064 mmol, 10.9% yield). TLC (DCM/MeOH=10/1,R_(f)=0.4): ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=1.8 Hz, 1H), 8.05 (d,J=8.6 Hz, 1H), 7.95 (dd, J=8.6, 1.8 Hz, 1H), 7.75-7.61 (m, 2H),7.55-7.37 (m, 3H), 4.63-4.50 (m, 2H), 4.27 (q, J=6.9 Hz, 2H), 3.96-3.53(m, 10H), 3.37-3.31 (m, 2H), 1.56-1.45 (m, 3H), 1.39 (t, J=7.3 Hz, 3H);ES-LCMS m/z 561.1 (M+H).

Example 22N-(2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 2,5-Difluoroaniline

To a solution of 1,4-difluoro-2-nitrobenzene (500 mg, 3.14 mmol) in MeOH(20 mL) was added Pd/C (66.9 mg, 0.629 mmol) in portions. Then themixture was stirred under a H₂ atmosphere at 20° C. for 1 h. After TLC(PE/EA=3/1) analysis showed the starting material had disappeared, themixture was filtered. The filtrate was concentrated to give the desiredproduct 2,5-difluoroaniline (338 mg, 2.61 mmol, 83% yield). ¹H NMR: (400MHz, CDCl₃) δ 6.94-6.88 (m, 1H), 6.50-6.46 (m, 1H), 6.40-6.31 (m, 1H),3.82 (br. s., 2H).

Step 2: 2-(4-Bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (180 mg, 0.775mmol) and 2,5-difluoroaniline (100 mg, 0.775 mmol) in DCM (20 mL) wasadded Et₃N (0.324 mL, 2.324 mmol) and HATU (884 mg, 2.324 mmol) inportions. Then the mixture was stirred at 20° C. for 3 h. After LCMSanalysis showed the starting material had disappeared, the solvent wasremoved in vacuo. Then the crude product was dissolved in DCM and washedwith H₂O and brine. The organic layer was evaporated to dryness. Thecrude product which was purified by silica column chromatography (PE/EA100/1 to 10/1) to afford2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (103 mg,0.276 mmol, 35.6% yield). ¹H NMR: (400 MHz, CD₃OD) δ 7.87-7.82 (m, 1H),7.39-7.26 (m, 3H), 7.20-7.13 (m, 1H), 6.90-6.82 (m, 1H), 3.83 (s, 2H);ES-LCMS: m/z 343.9 (M+H).

Step 3:N-(2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a solution of2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (40 mg, 0.116mmol),3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(44.8 mg, 0.116 mmol) and Cs₂CO₃ (114 mg, 0.349 mmol) in 1,4-dioxane (3mL) and H₂O (1 mL) was added PdCl₂(dppf) (8.51 mg, 0.012 mmol) in onecharge. Then the mixture was stirred at 110° C. in a microwave for 30min. After LCMS analysis showed the starting material had disappeared,the mixture was filtered. The filtrate was concentrated and evaporatedto dryness to give crude product which was dissolved in DCM and washedwith H₂O and brine. Then the crude product was purified by preparativeTLC to giveN-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(45.0 mg, 0.054 mmol, 46.1% yield). ¹H NMR: (400 MHz, CD₃OD) δ 7.96 (d,J=2.0 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.36-7.44(m, 5H), 7.18 (m, 1H), 6.91 (d, J=8.6 Hz, 2H), 6.87 (br. s., 1H), 5.37(s, 2H), 4.15-4.13 (m, 2H), 3.88 (s, 2H), 3.79 (s, 3H), 1.43 (t, J=7.0Hz, 3H); ES-LCMS: m/z 403.0 (M-120+H).

Step 4:N-(2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

A solution ofN-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(45 mg, 0.086 mmol) in HCl (MeOH (solvate), 64.6 μl, 0.258 mmol) wasstirred at 20° C. for 1 h. After LCMS analysis showed the startingmaterial had disappeared, the solvent was removed in vacuo to give crudeproduct which was purified by preparation HPLC to afford pure productN-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(5.83 mg, 0.014 mmol, 16.8% yield): ¹H NMR: (400 MHz, CD₃OD) δ 7.86(broad s, 1H), 7.43-7.37 (m, 5H), 7.20-7.13 (m, 1H), 6.86 (t, J=8.4 Hz,1H), 4.20-4.15 (m, 2H), 3.88 (s, 2H), 1.48 (t, J=7.0 Hz, 3H); ES-LCMS:m/z 403.0 (M+H).

Examples 23-26 (Table 1) were prepared using procedures analogous tothose described in example 17, starting from3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Intermediate 1), 2-(4-bromo-2-fluorophenyl)acetic acid (Intermediate4), and a variety of anilines.

TABLE 1 Example Structure NMR LCMS 23

¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1 H), 7.86 (d, J = 8.60 Hz, 1 H),7.53 (d, J = 8.60 Hz, 1 H), 7.46-7.26 (m, 5 H), 4.16- 4.11 (m 2 H), 3.81(s, 2 H), 1.47 (t, J = 6.62 Hz, 3 H) ES-LCMS m/z 478.1 (M + H) 24

¹H NMR: (400 MHz, CD₃OD) δ 8.32 (t, J = 8.0 Hz, 1H), 7.45- 7.40 (m, 1H),7.39-7.29 (m, 4H), 7.25 (s, 1H), 4.14 (m, 2H), 3.87 (s, 2H), 1.47 (t, J= 7.0 Hz, 3H) ES-LCMS: m/z 471.0 (M + H) 25

¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 2H), 7.64 (s, 1H), 7.42 (m, 1H),7.36-7.29 (m, 3H), 7.22 (s, 1H), 4.11 (m, 2H), 3.83 (s, 2H), 1.45 (t, J= 6.8 Hz, 3H) ES-LCMS m/z 503.0 (M + H) 26

¹H NMR (400 MHz, CD₃OD) δ: 8.39 (d, J = 5.51 Hz, 1H), 7.45 (d, J = 7.50Hz, 1H), 7.38- 7.43 (m, 1H), 7.25-7.38 (m, 4H), 7.23 (d, J = 2.21 Hz,1H), 4.12 (q, J = 6.98 Hz, 2H), 3.88 (s, 2H), 1.46 (t, J = 6.95 Hz, 3H)ES-LCMS m/z 453.0 (M + H)

Example 272-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

Step 1: 2-Chloro-4-ethoxypyridine

To a mixture of 2-chloro-4-nitropyridine (20 g, 126 mmol) in THF (200mL) was added sodium ethoxide (25.8 g, 378 mmol) in portions. Themixture was stirred at 25° C. for 10 h. The mixture was filtered and thefiltrate was concentrated. The crude material was purified by silicacolumn chromatography (PE/EA=5:1). All fractions found to containproduct by TLC (PE/EA=5:1, R_(f)=0.6) were combined and concentrated toyield a light yellow solid of 2-chloro-4-ethoxypyridine (13 g, 71.9mmol, 57% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=5.2 Hz, 1H), 6.82(d, J=2.4 Hz, 1H), 6.73 (dd, J=2.0, 6.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H),1.44 (t, J=7.2 Hz, 3H); ES-LCMS m/z 158 (M+H).

Step 2: 5-Bromo-2-chloro-4-ethoxypyridine

To a mixture of 2-chloro-4-ethoxypyridine (13 g, 82 mmol) and H₂SO₄ (40mL, 750 mmol) was added NBS (17.62 g, 99 mmol). Then the mixture wasstirred at 60° C. for 10 h. After cooling to rt, the mixture was pouredinto cold water (300 mL). The mixture was extracted with EA (200 mL×2).The combined organic layer was washed with saturated NaHCO₃ solution(200 mL×2) and concentrated. The crude material was purified by silicacolumn chromatography (PE/EA=15:1). All fractions found to containproduct by TLC (PE/EA=5:1, R_(f)=0.6) were combined and concentrated toyield a yellow solid of 5-bromo-2-chloro-4-ethoxypyridine (8.5 g, 26.3mmol, 32% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 6.79 (s, 1H),4.16 (q, J=6.8 Hz, 2H), 1.50 (t, J=6.8 Hz, 3H); ES-LCMS m/z 238 (M+3).

Step 3: 5-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

A mixture of 5-bromo-2-chloro-4-ethoxypyridine (8 g, 33.8 mmol), Cs₂CO₃(33.1 g, 101 mmol) and (4-methoxyphenyl)methanol (5.37 g, 38.9 mmol) inDMF (100 mL) was stirred at 120° C. for 12 h. The mixture was thenconcentrated. The residue was added to DCM (150 mL). The mixture wasfiltered and the filtrate was concentrated. The crude material waspurified by silica column chromatography (PE/EA=8:1). All fractionsfound to contain product by TLC (PE/EA=5:1, Rf=0.4) were combined andconcentrated to yield a yellow solid of5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (5 g, 12.57 mmol, 37%yield): ¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.32 (d, J=8.8 Hz, 1H),6.84 (d, J=8.4 Hz, 1H), 6.17 (s, 1H), 5.18 (s, 2H), 4.02 (q, J=6.8 Hz,2H), 3.74 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ES-LCMS m/z 338 (M+H).

Step 4:2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a mixture of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (279 mg,1.100 mmol) and2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(300 mg, 0.733 mmol) in 1,4-dioxane (50 mL) was added KOAc (216 mg, 2.2mmol) and PdCl₂(dppf) (26.8 mg, 0.037 mmol) under N₂. Then the mixturewas stirred at 100° C. for 5 h. The mixture was filtered and thefiltrate was concentrated. The crude material was purified bypreparative TLC (PE/EA=3:1, R_(f)=0.5) to yield a yellow solid of2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(230 mg, 0.403 mmol, 55% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.63-7.48 (m, 2H), 7.35-7.29 (m, 1H), 6.43 (s, 1H), 3.84-3.76 (m, 2H),1.53-1.49 (m, 6H), 1.34 (s, 9H); ES-LCMS m/z: 457 (M+H).

Step 5:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a mixture of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (74.1mg, 0.219 mmol) and2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(100 mg, 0.219 mmol) in water (1 mL) and 1,4-dioxane (3 mL) was addedCs₂CO₃ (143 mg, 0.438 mmol) and PdCl₂(dppf) (16.04 mg, 0.022 mmol) underN₂. Then the mixture was stirred and irradiated in a microwave oven at120° C. for 20 min. The mixture was then concentrated. The crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.4) to yieldan off white solid of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(70 mg, 0.071 mmol, 33% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.34 (m,2H), 7.30-7.17 (m, 4H), 6.92-6.88 (m, 2H), 6.45 (s, 1H), 6.38 (d, J=4.0Hz, 1H), 5.27 (s, 2H), 4.13-4.10 (m, 2H), 3.83-3.82 (m, 2H), 3.79-3.77(m, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 588 (M+H).

Step 6:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

A mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(70 mg, 0.119 mmol) and TFA (10% in DCM, 50 mL) was stirred at 25° C.for 2 h. The mixture was concentrated. The crude material was purifiedby preparative HPLC (MeCN/H₂O as eluants, basic condition) to give awhite solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(24.61 mg, 0.051 mmol, 43% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.32(m, 1H), 7.26-7.18 (m, 1H), 6.37 (s, 1H), 5.99 (s, 1H), 4.10 (q, J=6.8Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMSm/z: 468 (M+H).

Example 282-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

Step 1: 3-Bromo-5-ethoxypyridine

A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K₂CO₃ (111 g, 805mmol), iodoethane (69.0 g, 443 mmol) in DMF (900 mL) was stirred for 16h at 25° C. Then the mixture was concentrated and water (100 mL) wasadded, the mixture was extracted with DCM (400 mL×2), the combinedorganic phase were dried over Na₂SO₄, filtered, and concentrated to give3-bromo-5-ethoxypyridine (53 g, 218 mmol, 54% yield): ¹H NMR (400 MHz,CD₃OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40(t, J=7.0 Hz, 3H); ES-LCMS m/z 202 (M+H).

Step 2: 3-Bromo-5-ethoxypyridine-1-oxide

To a solution of 3-bromo-5-ethoxypyridine (53 g, 262 mmol) in DCM (600mL) at 0° C. was slowly added m-CPBA (67.9 g, 393 mmol) over 30 min.After the resulting solution was stirred for 15 h, the mixture waswashed with Na₂S₂O₃ solution and extracted with DCM (600 mL×2). Thecombined organic layer was washed with saturated NaHCO₃ (300 mL), brine(300 mL), dried over Na₂SO₄, filtered, and concentrated to give3-bromo-5-ethoxypyridine-1-oxide (40 g, 165 mmol, 63% yield): ¹HNMR (400MHz, CD₃OD) δ 8.19-8.18 (m, 1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m, 1H),4.17-4.15 (d, J=8.8 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); ES-LCMS m/z 217(M+H).

Step 3: 5-Bromo-2-chloro-3-ethoxypyridine

To a solution of 3-bromo-5-ethoxypyridine-1-oxide (40 g, 183 mmol) inDCM (200 mL) at 0° C. was slowly added POCl₃ (159 mL, 1701 mmol) over 30min. Then the resulting solution was warmed to 45° C. and stirred for 15h. The mixture was concentrated and adjusted pH=9-10 with 10% NaOHsolution, extracted with DCM (300 mL×2), dried over Na₂SO₄, filtered,and concentrated to give the crude product which was purified by silicacolumn chromatography (10% EA: 90% PE, 800 g silica column). Allfractions found to contain product by TLC (EA: PE=1:5, R_(f)=0.6) werecombined and concentrated to yield an oil of5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9 mmol, 33% yield): ¹H NMR(400 MHz, CD₃OD) δ 8.00-7.99 (d, J=2.0 Hz, 1H), 7.65-7.64 (d, J=2.0 Hz,1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).

Step 4: 5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF(300 mL) was added NaH (3.96 g, 165 mmol) at 0° C. dropwise. After themixture was stirred for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g,110 mmol) in DMF (100 mL) was added to above mixture and the mixture wasstirred for 12 h at 80-90° C. The mixture was quenched by H₂O (20 mL),extracted with DCM (400 mL×2), dried over Na₂SO₄, filtered, andconcentrated to give the residue which was purified by columnchromatography (10% EA: 90% PE, 360 g silica column). All fractionsfound to contain product by TLC (EA: PE=1:5, R_(f)=0.5) were combinedand concentrated to yield a white solid of5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (36 g, 74.5 mmol, 68%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.36-7.31 (m,3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H),2.37 (d, J=7.0 Hz, 3H); ES-LCMS m/z 338 (M+H).

Step 5:3-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (10g, 29.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.26 g,32.5 mmol) and KOAc (7.25 g, 73.9 mmol) in 1,4-dioxane (250 mL) stirredunder nitrogen at 20° C. was added PdCl₂(dppf) (1.082 g, 1.478 mmol) inone charge. The reaction mixture was stirred at 100° C. for 3 h. Themixture was filtered and the filtrate was concentrated in vacuo to givethe crude product. The crude material was purified by silica columnchromatography (PE/EA=10:1). All fractions found to contain product byTLC (PE/EA=10:1, R_(f)=0.6) were combined and concentrated to yield awhite solid of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.2g, 23.88 mmol, 81% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.42(d, J=8.8 Hz, 2H), 7.33 (s, 1H), 6.88-6.85 (m, 2H), 5.45 (s, 2H),4.11-4.06 (m, 2H), 3.78 (s, 3H), 1.43 (t, J=7.0 Hz, 3H), 1.33 (s, 12H);ES-LCMS m/z 386.0 (M+H).

Step 6:2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a mixture of3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(200 mg, 0.519 mmol) and2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(212 mg, 0.519 mmol) in water (1 mL) and 1,4-dioxane (3 mL) was addedCs₂CO₃ (338 mg, 1.038 mmol) and PdCl₂(dppf) (38.0 mg, 0.052 mmol) underN₂. Then the mixture was stirred and irradiated in a microwave oven at120° C. for 20 min. The mixture was then concentrated. The crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.4) to yielda off white solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(100 mg, 0.121 mmol, 23% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.28 (m,5H), 7.27-7.21 (m, 2H), 6.92-6.84 (m, 2H), 6.36 (s, 1H), 4.50 (s, 2H),4.11 (d, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.79-3.75 (m, 3H), 1.52 (s, 6H),1.45 (t, J=7.2 Hz, 3H); ES-LCMS m/z 468 (M-119).

Step 7:2-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

A mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(100 mg, 0.170 mmol) and TFA (10% in DCM, 100 mL) was stirred at 25° C.for 2 h. The mixture was then concentrated. The crude material waspurified by preparative HPLC (MeCN/H₂O as eluants, acid condition) togive a white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(28.35 mg, 0.060 mmol, 36% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.30(m, 4H), 7.25 (d, J=1.6 Hz, 1H), 6.36 (s, 1H), 4.12 (q, J=6.8 Hz, 2H),3.82 (s, 2H), 1.52 (s, 6H), 1.46 (t, J=6.8 Hz, 3H); ES-LCMS m/z 468(M+H).

Example 292-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

Step 1: Methyl 3-nitro-5-(trifluoromethyl)benzoate

To a mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (20 g, 85 mmol)in MeOH (200 mL) was added H₂SO₄ (12 mL, 225 mmol) at 0° C. dropwise,then the mixture was stirred for 16 h at 25° C. Then the solvent wasconcentrated and was adjusted pH=9 with NaHCO₃ solution. The solvent wasconcentrated to give the residue which was extracted with DCM (200mL×2), dried over Na₂SO₄, filtered, and concentrated to yield an oil ofmethyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 76 mmol, 90% yield):¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 4.01(s, 3H); ES-LCMS m/z 250 (M+1).

Step 2: 3-Nitro-5-(trifluoromethyl)benzohydrazide

A mixture of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 80 mmol)and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirredfor 16 h at 25° C. Then the solvent was concentrated to yield an offwhite solid of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 72.2mmol, 90% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.65 (s, 1H),8.50 (s, 1H); ES-LCMS m/z 250 (M+H).

Step 3: 2-Methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole

A mixture of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 80 mmol)in 1,1,1-triethoxyethane (156 g, 963 mmol) was heated to reflux andstirred for 12 h. Then the solvent was concentrated to yield a blacksolid of 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole(20 g, 65.9 mmol, 82% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.04 (s, 1H),8.71 (s, 1H), 8.66 (s, 1H), 2.67 (s, 1H); ES-LCMS m/z 274 (M+H).

Step 4: 2-Methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole

A mixture of2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (20 g,73.2 mmol) and Pd/C (0.779 g, 7.32 mmol) in MeOH (25 mL) was stirred for12 h at 35 psi under H₂ atmosphere at 25° C. Then the mixture wasfiltered and the filtrate was concentrated to give the residue which wascrystallized with MeOH (15 mL) to yield a gray solid of3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (17 g, 66.4mmol, 91% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.42 (s, 1H),7.07 (s, 1H), 2.61 (s, 3H); ES-LCMS m/z 244 (M+H).

Step 5:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

To a mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (300 mg, 0.729 mmol),3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (195 mg,0.802 mmol), and Et₃N (0.203 ml, 1.458 mmol) in DCM (15 ml) was addedHATU (333 mg, 0.875 mmol) at 25° C. Then the mixture was stirred for 2h, the mixture was concentrated to give the residue which was extractedwith DCM (30 mL×2). The organic extract was washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by preparative TLC (DCM: MeOH=30:1, R_(f)=0.7) to yield2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide(60 mg, 0.094 mmol, 13% yield): ¹H NMR (400 MHz, MeOD-d4) δ 8.52 (br.s., 1H), 7.99 (br. s., 1H), 7.95 (br. s., 1H), 7.42-7.39 (m, 2H), 7.30(d, J=8.4 Hz, 3H), 6.89 (d, J=8.6 Hz, 3H), 6.52-6.50 (m, 1H), 5.11 (br.s., 2H), 4.64-4.62 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 2.63 (br. s., 3H),1.38 (t, J=7.1 Hz, 3H); ES-LCMS m/z 637 (M+H).

Step 6:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

A mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide(60 mg, 0.094 mmol) and Pd/C (10.03 mg, 0.094 mmol) in MeOH (15 mL) wasstirred for 0.5 h under a H₂ atmosphere at 25° C. Then the mixture wasfiltered and the filtrate was concentrated to give the residue which waspurified by preparative HPLC to yield2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide(41.53 mg, 0.079 mmol, 84% yield): ¹H NMR (400 MHz, DMSO-d6)611.40-11.29 (m, 1H), 10.86 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 7.86(s, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J=2.6 Hz, 2H), 5.78 (s, 1H), 4.02(q, J=7.1 Hz, 2H), 3.79 (s, 2H), 2.58 (s, 3H), 1.26 (t, J=6.9 Hz, 3H);ES-LCMS m/z 517 (M+H).

Example 302-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxopentanenitrile

To a mixture of MeCN (13.9 mL, 264 mmol) in THF (500 mL) cooled to −78°C. was added n-BuLi (106 mL, 264 mmol). The mixture was stirred at −30°C. for 0.5 h. Then to the mixture was added methyl3,3,3-trifluoro-2,2-dimethylpropanoate (30 g, 176 mmol) dropwise. Themixture was stirred at 25° C. for 10 h. The mixture was quenched withaqueous NH₄Cl (50 mL), extracted with EA (300 mL×3). The organic layerwas dried over Na₂SO₄, filtered and concentrated to yield a crudeproduct of a yellow oil of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (22 g, 122.9 mmol, 70%yield): ¹H NMR (400 MHz, CDCl₃) δ 3.75 (s, 2H), 1.41 (s, 6H).

Step 2: 5-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-3-amine

To a mixture of hydroxylamine hydrochloride (23.2 g, 336 mmol) in water(300 mL) cooled to 0° C. was added NaHCO₃ (30 g, 351 mmol) and pH=7.5adjusted. Then to the mixture was added a solution of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (30 g, 167.4 mmol) inMeOH (40 mL). The mixture was stirred at 65° C. for 15 h. After cooled,the mixture was acidified with conc. HCl to pH=1 and then refluxed for 2h. After cooling to rt, the mixture was neutralized by 4 M NaOH to pH=8.The mixture was extracted with EA (300 mL×2). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude material waspurified by silica column chromatography (PE/EA=8:1˜3:1). All fractionsfound to contain product by TLC (PE/EA=2:1, R_(f)=0.6) were combined andconcentrated to yield a red solid of5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (19.5 g, 100.5mmol, 60% yield): ¹H NMR (400 MHz, CDCl₃) δ 5.79 (s, 1H), 3.96 (s., 2H),1.53 (s, 6H); ES-LCMS m/z: 195 (M+H).

Step 3:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

To a mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (55.1 g, 134 mmol) and5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (26 g, 134 mmol)in pyridine (500 mL) was added T₃P® (137.5 mL, 134 mmol) dropwise andstirred at 25° C. for 1 h. After TLC analysis showed the startingmaterial was consumed completely, the mixture was poured into stirringcold water (1 L). The mixture was stirred for 0.5 h and then let standfor 10 h. The solid was filtered, washed with H₂O (200 mL×3) and TBME(200 mL×2) and dried in vacuo to give an off-white solid of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(65 g, 100 mmol, 74% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H),7.40-7.32 (m, 3H), 7.26 (d, J=9.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 3H), 6.43(s, 1H), 5.26 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 3.78 (s,3H), 1.56 (s, 6H), 1.35 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 588 (M+H).

Step 4:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide

To a suspension of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(100 g, 170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol)dropwise. The mixture was stirred at 25° C. for 2 h. The mixture wasthen concentrated. To the residue was added H₂O (500 mL) dropwise andthen neutralized with saturated Na₂CO₃ solution to adjust pH=7.5. Theprecipitate was filtered, washed with H₂O (350 mL×3) and dried in vacuo.To the solid was added PE/EA (3:1, v/v, 300 mL) and stirred for 0.5 h.The solid was filtered and washed with PE/EA (3:1, v/v, 100 mL×2). Thesolid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L) and thenconcentrated in vacuo to a minimal amount of solvent (about 150 mL). Thesolid was filtered, washed with CH₃CN (50 mL×2) and dried in vacuo. Theresidual solid was added to EtOH (2.5 L) and heated to 80° C. After thesolid was dissolved completely, the mixture was concentrated in vacuo togive a white solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide(61.4 g, 131 mmol, 77% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.30 (m,2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J=7.2 Hz,2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMS m/z:468 (M+H).

Example 312-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (10 g, 61.3mmol) in H₂SO₄ (50 mL, 938 mmol), nitric acid (3.01 ml, 67.4 mmol) wasadded dropwise. After 30 min, the ice bath was removed and the reactionwas stirred at 25° C. for 72 h. The reaction mixture was added to ice.

The resulting precipitate was collected by filtration, rinsed withadditional water, and air-dried to afford the first batch of product.Another crop of product was obtained after evaporating the mother liquorto less than 100 mL, cooling on an ice bath, and adding NaOH to pHadjust to 8. The mixture was extracted by EA (100 mL). The organic layerwas dried and concentrated to give the product, which was combined withthe first batch to yield a yellow solid of5-nitro-3-(trifluoromethyl)pyridin-2-ol (9 g, 39.9 mmol, 65% yield): ¹HNMR (400 MHz, CD₃OD) δ 8.84 (d, J=2.8 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H);ES-LCMS m/z: 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

To a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (9 g, 43.2mmol) in SOCl₂ (30 mL, 411 mmol) was added a catalytic amount of DMF(0.033 ml, 0.432 mmol). The mixture was stirred at 80° C. overnight.After LCMS analysis showed the starting material was consumed, thesolvent was removed in vacuo. The residue was dissolved in H₂O andextracted with EA. The organic layer was washed with aqueous NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby column chromatography (PE/EA=10/1) to yield a yellow oil of2-chloro-5-nitro-3-(trifluoromethyl)pyridine (8.5 g, 34.7 mmol, 80%yield): ¹H NMR (400 MHz, CD₃OD) δ9.43 (d, J=2.8 Hz, 1H), 8.92 (d, J=2.4Hz, 1H); ES-LCMS m/z: 225.2 (M+H).

Step 3: tert-Butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5 g,22.07 mmol) and K₂CO₃ (6.10 g, 44.1 mmol) in THF (150 mL) was addedtert-butyl 2-cyanoacetate (3.74 g, 26.5 mmol). The resulting mixture wasstirred at 70° C. overnight under N₂. After TLC analysis (PE/EA=10/1)showed the starting material was consumed, the solvent was removed invacuo. The residue was dissolved in EA (100 mL) and washed with H₂O (50mL) and brine (50 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated to yield a solid of tert-butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13mmol, 96% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 8.59 (br. s.,1H), 4.63 (br. s., 1H), 1.55 (s, 9H); ES-LCMS m/z: 332.1 (M+H).

Step 4: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

To a solution of tert-butyl2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13mmol) in MeOH (100 mL) was added aqueous HCl (40 mL, 1316 mmol). Theresulting mixture was stirred at 100° C. overnight. After TLC analysis(PE/EA=10/1) showed the starting material was consumed, the solvent wasremoved in vacuo. The residue was dissolved in H₂O (50 mL) and extractedby EA (100 mL). The organic layer was washed with aqueous NaHCO₃ andbrine and then dried over Na₂SO₄. After filtration, the filtrate wasconcentrated to give the crude product, which was purified by columnchromatography (PE/EA=10/1) to yield a brown solid of2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (4.3 g, 17.77mmol, 84% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.59 (s, 1H), 8.88 (d, J=2.4Hz, 1H), 4.86 (s, 2H); ES-LCMS m/z: 232.1 (M+H).

Step 5:2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

To a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile(1 g, 4.33 mmol) and Cs₂CO₃ (4.23 g, 12.98 mmol) in MeCN (30 mL) wasadded iodomethane (3.07 g, 21.63 mmol).

The resulting mixture was stirred at 40° C. overnight in an autoclave.After LCMS analysis showed the starting material was consumed, thesolvent was removed in vacuo. The residue was dissolved in EA (100 mL)and washed with H₂O (50 mL) and brine (50 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product waspurified by column chromatography (PE/EA=10/1) to yield a yellow oil of2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (0.7g, 2.70 mmol, 62% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.56 (s, 1H), 8.93(d, J=2.8 Hz, 1H), 1.90 (s, 6H); ES-LCMS m/z: 260.1 (M+H).

Step 6: 2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal

To a solution of2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (700mg, 2.70 mmol) in DCM (30 mL) was added DIBAL-H (5.40 mL, 5.40 mmol) at−50° C. The resulting mixture was stirred at −50° C. for 1 h and slowlywarmed to rt. After LCMS analysis showed the starting material wasconsumed, the mixture was quenched by saturated NH₄Cl. The mixture wasdissolved in water and extracted by EA. The organic layer was dried andconcentrated to give the crude product, which was purified by columnchromatography to yield a yellow oil of2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal (200 mg,0.763 mmol, 28% yield): ¹H NMR (400 MHz, CD₃OD) δ 9.67 (s, 1H), 9.54 (s,1H), 8.89 (s, 1H), 1.56 (s, 6H); ES-LCMS m/z: 263.1 (M+H).

Step 7: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol

A solution of2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal (100 mg,0.381 mmol) and Raney nickel (22.39 mg, 0.381 mmol) in MeOH (30 mL) wasstirred at 25° C. under H₂ overnight. After TLC analysis (PE/EA=5/1)showed the starting material was consumed, the mixture was filtered. Thefiltrate was concentrated to give 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (60 mg, 0.256 mmol, 67% yield):¹H NMR (400 MHz, CD₃OD) δ 8.08 (br. s., 1H), 7.36 (d, J=2.8 Hz, 1H),1.31 (s, 6H); ES-LCMS m/z: 235.1 (M+H).

Step 8:2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

A solution of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (50 mg, 0.122 mmol),2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (28.5mg, 0.122 mmol), HATU (92 mg, 0.243 mmol) and DIEA (0.064 mL, 0.365mmol) in DCM (10 mL) was stirred at 25° C. After LCMS analysis showedthe starting material was consumed, the mixture was washed with H₂O. Theorganic layer was washed with brine and dried over Na₂SO₄ and filtered.The filtrate was concentrated to give the crude product, which waspurified by preparative TLC (DCM/MeOH=20/1) to yield2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide(20 mg, 0.032 mmol, 26% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.95 (br. s.,1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.43-7.39 (m, 3H), 7.30-7.24 (m, 2H),6.95-6.91 (m, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16-4.11 (m, 2H),3.87-3.79 (m, 6H), 1.40-1.38 (m, 9H); ES-LCMS m/z: 628.3 (M+H).

Step 9:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

A solution of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide(20 mg, 0.032 mmol) in TFA in DCM (5 mL, 3.72 mmol) was stirred at 25°C. After LCMS analysis showed the starting material was consumed, thesolvent was removed in vacuo to give the crude product, which waspurified by preparative HPLC (under neutral condition) to yield a whitesolid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide(8.8 mg, 0.017 mmol, 54% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.91 (s, 1H),8.46 (d, J=2.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.24-7.21 (m, 2H), 5.98 (s,1H), 4.13-4.08 (m, 2H), 3.82 (s, 4H), 1.37 (t, J=7.0 Hz, 9H); ES-LCMSm/z: 508.2 (M+H).

Example 322-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: 4-Ethoxypyridine 1-oxide

To a mixture of 4-nitropyridine 1-oxide (28 g, 200 mmol) in THF (50 mL)was added sodium ethanolate (40.8 g, 600 mmol). The mixture was stirredat 25° C. for 16 h. The reaction residue was then concentrated and thecrude material was purified by silica column chromatography(DCM/MeOH=25:1). All fractions found to contain product by TLC(DCM/MeOH=25:1, R_(f)=0.6) were combined and concentrated to yield adark red solid of 4-ethoxypyridine 1-oxide (20 g, 101 mmol, 50% yield).¹H NMR (400 MHz, MeOH-d₄) δ 8.20 (d, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz,2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 140.0(M+H).

Step 2: 4-Ethoxypyridin-2-ol

A mixture of 4-ethoxypyridine 1-oxide (20 g, 144 mmol) in Ac₂O (200 mL,7.836 mol) was heated to refluxed for 4 h. Then, the solvent was removedin vacuo, and the residue was dissolved in MeOH (50 mL) and water (50mL) and stirred at 25° C. for 16 h. The mixture was then concentratedand the crude material was purified by silica column chromatography(DCM/MeOH=10:1). All fractions found to contain product by TLC(DCM/MeOH=10:1, R_(f)=0.6) were combined and concentrated to yield adark yellow solid of 4-ethoxypyridin-2-ol (17 g, 104 mmol, 72% yield).¹H NMR (400 MHz, MeOH-d₄) δ 8.20 (d, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz,2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 140.0(M+H).

Step 3: 4-Ethoxy-5-iodopyridin-2-ol

To a mixture of 4-ethoxypyridin-2-ol (17 g, 122 mmol) in DMF (125 mL)was added NIS (27.5 g, 122 mmol). The mixture was stirred at 80° C. for16 h. The mixture was concentrated and purified by preparative HPLC(MeCN/H2O as eluants, acidic condition) to yield a yellow solid of4-ethoxy-5-iodopyridin-2-ol (4.2 g, 13.47 mmol, 11% yield). TLC(DCM/MeOH=10:1, R_(f)=0.6): ¹H NMR (400 MHz, MeOH-d₄) δ 7.70 (s, 1H),5.91 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 1.44 (t, J=6.8 Hz, 3H); ES-LCMSm/z: 265.9 (M+H).

Step 4: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

To a mixture of 4-ethoxy-5-iodopyridin-2-ol (3.7 g, 13.96 mmol) in THF(10 mL) was added (bromomethyl)benzene (2.87 g, 16.75 mmol) and silvercarbonate (7.70 g, 27.9 mmol). The mixture was stirred at 70° C. for 16h. The reaction residue was then filtered and the filtrate wasconcentrated. The mixture was diluted with water (30 mL) and extractedwith DCM (30 mL×2). The combined organic extract was washed with brine,dried over MgSO₄, filtered and concentrated. The crude material waspurified by silica column chromatography (PE/EA=5:1). All fractionsfound to contain product by TLC (PE/EA=5:1, R_(f)=0.6) were combined andconcentrated to yield a light yellow oil of2-(benzyloxy)-4-ethoxy-5-iodopyridine (4.2 g, 10.64 mmol, 76% yield). ¹HNMR (400 MHz, MeOH-d₄) δ 8.25 (s, 1H), 7.47-7.41 (m, 2H), 7.40-7.30 (m,3H), 6.41 (s, 1H), 5.32 (s, 2H), 4.16 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2Hz, 3H); ES-LCMS m/z 356.0 (M+H).

Step 5: Methyl 2-(4-bromo-3-fluorophenyl)acetate

To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (5 g, 21.46 mmol)in MeOH (50 mL) was added SOCl₂ (1.879 mL, 25.7 mmol) and DMF (0.166 mL,2.146 mmol). Then the mixture was stirred at 80° C. for 16 h. Themixture was concentrated and extracted with EA (100 mL×2) and washedwith NaHCO₃ (100 mL) to give the organic layer. The combined organicextract was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to yield a brown oil of methyl2-(4-bromo-3-fluorophenyl)acetate (5 g, 17.20 mmol, 80% yield): ¹H NMR(400 MHz, MeOH-d₄) δ 7.53 (t, J=7.6 Hz, 1H), 7.15 (dd, J=1.6, 9.6 Hz,1H), 7.04-6.99 (m, 1H), 3.67 (s, 3H), 3.65 (s, 2H); ES-LCMS m/z 249.0(M+H+2).

Step 6: Methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a mixture of methyl 2-(4-bromo-3-fluorophenyl)acetate (5 g, 20.24mmol) in 1,4-dioxane (10 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.65 g,22.26 mmol), KOAc (3.97 g, 40.5 mmol) and PdCl₂(dppf) (1.481 g, 2.024mmol). The resulting suspension was stirred at 110° C. for 16 h undernitrogen. The mixture was then filtered and concentrated. The crudematerial was purified by silica column chromatography (PE/EA=5:1). Allfractions found to contain product by TLC (PE/EA=5:1, R_(f)=0.6) werecombined and concentrated to yield a yellow oil of methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(6 g, 16.32 mmol, 81% yield): ¹H NMR (400 MHz, MeOH-d₄) δ 7.66-7.58 (m,1H), 7.07 (d, J=7.6 Hz, 1H), 6.98 (d, J=10.4 Hz, 1H), 3.67 (s, 5H), 1.33(s, 12H); ES-LCMS m/z 295.1 (M+H).

Step 7:2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aceticacid

To a mixture of methyl2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(5 g, 17 mmol) in THF (30 mL) and water (30 mL) was added LiOH.H₂O (3.57g, 85 mmol). The mixture was stirred at 25° C. for 16 h. Then thereaction residue was concentrated, diluted with EA (200 mL) and aqueousHCl was added. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. The crude material was purified bysilica column chromatography (PE/EA=2:1). All fractions found to containproduct by TLC (PE/EA=2:1, R_(f)=0.6) were combined and concentrated toyield a light yellow oil of2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenypaceticacid (5 g, 14.28 mmol, 84% yield): NMR (400 MHz, CD₃OD) δ 7.66 (t, J=6.8Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.03 (d, J=10.0 Hz, 1H), 3.66 (s, 2H),1.37 (s, 12H); ES-LCMS m/z 281.1 (M+H).

Step 8: Ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate

To a mixture of diisopropylamine (8.00 mL, 57.1 mmol) in THF (300 mL)cooled to 0° C., n-BuLi (24.60 mL, 61.5 mmol) was added dropwise. Themixture was stirred at 0° C. for 1 h. Then the mixture was cooled to−30° C. and a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF(2 mL) was added. The mixture was stirred at −30° C. for 1 h. To themixture was added a solution of1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5mL) at −30° C. The whole mixture was stirred at −30° C. for 3 h and thenstirred at 25° C. for 12 h. The mixture was quenched with aqueous NH₄Cland extracted with EA. The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby silica column chromatography (PE/EA=200:1). All fractions found tocontain product by TLC (PE/EA=10:1, R_(f)=0.6) were combined andconcentrated to yield a light yellow solid of ethyl2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 35.3 mmol,80% yield): ¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.0 Hz, 1H), 7.41 (t,J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.17 (q,J=7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s, 6H);ES-LCMS m/z 275 (M+H).

Step 9: Ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate

To a solution of ethyl2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 36.5 mmol)in H₂SO₄ (5 mL, 94 mmol) cooled to 0° C. was added potassiumnitroperoxous acid (4.05 g, 40.1 mmol) in portions. The mixture wasstirred at 0° C. for 30 min. The mixture was poured into ice-water andthen extracted with DCM (100 mL×2). The organic layer was washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give a yellowsolid of ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g,24.54 mmol, 67% yield): NMR (400 MHz, CDCl₃) δ: 8.59 (d, J=2.4 Hz, 1H),8.47 (dd, J=2.4, 8.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 5.97-5.83 (m, 2H);ES-LCMS m/z 320 (M+H).

Step 10: Ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

A reaction mixture of ethyl2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g,26.6 mmol) and Pd/C (0.283 g, 2.66 mmol) in MeOH (50 mL) washydrogenated using an H-cube apparatus (settings: 50° C., 50 psi, 24 h).The mixture was filtered, and the filtrate was concentrated. The crudematerial was purified by silica column chromatography (PE/EA=10:1). Allfractions found to contain product by TLC (PE/EA=5:1, R_(f)=0.4) werecombined and concentrated to yield an off white solid of ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7 g, 22.42mmol, 84% yield): ¹H NMR (400 MHz, CDCl₃) δ 6.98 (d, J=8.4 Hz, 1H), 6.91(d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 8.4 Hz, 1H), 4.15 (q, J=6.8 Hz, 2H),3.00 (s, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290(M+H).

Step 11: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

To a mixture of ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91mmol) in THF (200 mL) was added LAH (0.525 g, 13.83 mmol) in portions.The mixture was stirred at 25° C. for 10 h. The mixture was quenchedwith 15% aqueous NaOH solution (10 mL). The mixture was dried overNa₂SO₄, filtered, and the filtrate was concentrated. The residue waspurified by silica column chromatography (PE/EA=8:1). All fractionsfound to contain product by TLC (PE/EA=2:1, R_(f)=0.35) were combinedand concentrated to yield a light yellow oil of3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (1.1 g,4.45 mmol, 64% yield): ¹H NMR (400 MHz, CD₃Cl) δ: 7.17 (d, J=8.4 Hz,1H), 6.98 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.4, 8.0 Hz, 1H), 3.31 (s, 2H),2.67 (d, J=1.2 Hz, 2H), 0.84 (s, 6H); ES-LCMS m/z 248 (M+H).

Step 12:4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline

To a mixture of3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg,1.213 mmol) in DCM (150 mL) was added imidazole (124 mg, 1.820 mmol) andTBSCl (219 mg, 1.456 mmol). Then the mixture was stirred at 25° C. for 5h. The mixture was filtered and the filtrate was concentrated. The crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.5) to yielda light yellow solid of4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline(350 mg, 0.930 mmol, 77% yield): ¹H NMR (400 MHz, CDCl₃) δ: 7.14 (d,J=8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.70 (dd, J=2.8, 8.4 Hz, 1H),3.20 (s, 2H), 2.62 (d, J=1.2 Hz, 2H), 0.87 (s, 9H), 0.73 (s, 6H), 0.00(s, 6H); ES-LCMS m/z 362 (M+H).

Step 13:N-(4-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

To a solution of2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aceticacid (5 g, 17.85 mmol) in DCM (100 mL) was added4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline(7.10 g, 19.64 mmol), DIEA (6.24 mL, 35.7 mmol) and HATU (8.14 g, 21.42mmol). The solution was stirred at 25° C. for 16 h. Then the reactionmixture was concentrated to give the crude product, which was purifiedby silica column chromatography (PE/EA=8:1). All fractions found tocontain product by TLC (PE/EA=8:1, R_(f)=0.6) were combined andconcentrated to yield a white solid ofN-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(10 g, 12.83 mmol, 72% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.83 (d, J=2.0Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 6.99 (dd, J=4.8, 10.0 Hz, 2H), 3.63 (s,2H), 3.26 (s, 2H), 2.69 (s, 2H), 1.11 (s, 12H), 0.86 (s, 9H), 0.73 (s,6H), 0.00 (s, 6H); ES-LCMS m/z 624.2 (M+H).

Step 14:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

To a mixture of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (3.2 g, 9.01 mmol)in 1,4-dioxane (60 mL) and water (20 mL) was addedN-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(6.18 g, 9.91 mmol), Cs₂CO₃ (5.87 g, 18.02 mmol) and PdCl₂(dppf) (0.659g, 0.901 mmol). The mixture was stirred under nitrogen at 110° C. for 16h. Then the reaction residue was filtered and the filtrate wasconcentrated to give the crude product, which was purified by silicacolumn chromatography (PE/EA=5:1). All fractions found to containproduct by TLC

(PE/EA=5:1, R_(f)=0.6) were combined and concentrated to yield a lightyellow oil of24446-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2g, 5.21 mmol, 58% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=2.0 Hz,1H), 7.88 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.47 (d, J=6.0 Hz, 3H),7.42-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.17 (m, 2H), 6.50 (s, 1H),5.38 (s, 2H), 4.16-4.12 (m, 2H), 3.77 (s, 2H), 3.36 (s, 2H), 2.81 (s,2H), 1.32 (t, J=6.8 Hz, 3H), 0.97 (s, 9H), 0.85 (s, 6H), 0.12 (s, 6H);ES-LCMS m/z 725.2 (M+H).

Step 15:2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

To a mixture of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilypoxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(4.5 g, 4.83 mmol) in DCM (30 mL) was added TFA (4.46 mL, 57.9 mmol).The mixture was stirred at 25° C. for 2 h. Then the reaction residue wasconcentrated, added to MeCN (50 mL), made basic with NH₄OH andconcentrated. The crude material was purified by silica columnchromatography (PE/EA=1:1). All fractions found to contain product byTLC (PE/EA=1:1, R_(f)=0.6) were combined and concentrated to yield alight yellow solid of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(4.2 g, 4.19 mmol, 87% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.97 (s, 1H),7.88 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.51-7.43 (m, 3H), 7.38 (t, J=7.2Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.16 (m, 2H), 6.50 (s, 1H), 5.38 (s,2H), 4.14-4.11 (m, 2H), 3.77 (s, 2H), 2.80 (s, 2H), 2.03 (s, 2H), 1.32(t, J=6.8 Hz, 3H), 0.86 (s, 6H); ES-LCMS m/z 611.2 (M+H).

Step 16:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

To a mixture of2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(4.2 g, 6.88 mmol) in MeOH (50 mL) was added Pd/C (10%, 420 mg). Themixture was stirred under H₂ at 25° C. for 16 h. Then the reactionresidue was filtered and concentrated. The crude material was purifiedby preparative HPLC (MeCN/H₂O as eluants, acidic condition) to yield awhite solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide(2000.18 mg, 3.84 mmol, 61% yield). TLC (DCM/MeOH=10:1, R_(f)=0.6): ¹HNMR (400 MHz, CD₃OD) δ 7.94 (s, 1H), 7.77-7.68 (m, 2H), 7.42 (d, J=8.8Hz, 1H), 7.37-7.29 (m, 1H), 7.27-7.17 (m, 2H), 6.36 (s., 1H), 4.25-4.15(m, 2H), 3.75 (s, 2H), 2.76 (s, 2H), 1.33 (t, J=6.8 Hz, 3H), 0.82 (s,6H); ES-LCMS m/z 521.2 (M+H).

Example 332-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide

Step 1:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

To a solution of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (0.5 g, 1.215 mmol) in MeOH (10 mL) stirred under nitrogen at 20°C. was added Pd/C (0.013 g, 0.122 mmol) in one charge. The reactionmixture was reacted with a H₂ balloon at 20° C. for 12 h.

The mixture was filtered, and the filtrate was concentrated in vacuo togive the crude2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(0.4 g, 1.373 mmol). TLC (DCM/MeOH=10:1, R_(f)=0.2): ¹H NMR (400 MHz,DMSO-d₆) δ 7.32-7.15 (m, 4H), 5.78 (s, 1H), 4.01-4.00 (m, 2H), 3.59 (s,2H), 1.26-1.23 (m, 3H); ES-LCMS m/z 292 (M+H).

Step 2:2-(4-(4-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide

A solution of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid(80 mg, 0.275 mmol), 3-(trifluoromethyl)aniline (44.3 mg, 0.275 mmol),HATU (125 mg, 0.330 mmol) and DIEA (0.048 mL, 0.275 mmol) in DMF (10 mL)was stirred at rt for 5 h. After LCMS analysis showed the startingmaterial had disappeared, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in DCM and washed with H₂Oand brine. The organic layer was evaporated to dryness to give crudeproduct which was purified by preparative HPLC to give pure product2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide(14.56 mg, 0.032 mmol, 12% yield) as a yellow solid. ¹H NMR (400 MHz,CD₃OD): δ 8.03 (br. s., 1H), 7.77 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.51(t, J=8.0 Hz, 1H), 7.46-7.36 (m, 2H), 7.31-7.24 (m, 2H), 6.28 (s, 1H),4.24-4.19 (m, 2H), 3.84 (s, 2H), 1.41 (t, J=6.8 Hz, 3H); ES-LCMS: m/z435.1 (M+H).

Example 342-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

Step 1: 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole

To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg,2.391 mmol) and K₂CO₃ (496 mg, 3.59 mmol) in DMF (3 mL) was added4-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then themixture stirred under N₂ was heated to 110° C. and reacted for 15 h.LCMS analysis showed the starting material disappeared. The solvent wasremoved in vacuo. The residue was dissolved in DCM (60 mL) and washedwith H₂O (20 mL) and brine (20 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated to give crude material which waspurified by silica column chromatography (PE/EA=10/1 to 5/1) to affordpure product 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole(500 mg, 1.678 mmol, 70.2% yield): ¹H NMR (400 MHz, CD₃OD): δ 8.83 (s,1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 2.18 (s,3H). ES-LCMS: m/z 272.2 (M+H).

Step 2: 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline

To a solution of4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (560 mg,2.065 mmol) in MeOH (10 mL) was added Pd/C (21.98 mg, 0.206 mmol) in oneportion. Then the mixture was stirred under H₂ for 12 h. LCMS analysisshowed the starting material disappeared. The suspension was filteredthrough a pad of Celite® and the filter cake was washed with MeOH (2mL). The combined filtrates were concentrated to dryness to give crudeproduct, which was purified by preparative TLC (PE/EA=5/1, R_(f)=0.25)to afford pure product3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (280 mg, 1.158mmol, 56.1% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.96 (s, 1H), 7.52 (s,1H), 7.15 (s, 2H), 6.82 (s, 1H), 2.15 (s, 3H). ES-LCMS: m/z 242.1 (M+H).

Step 3:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide

To a solution of 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline(160 mg, 0.663 mmol) and2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (274 mg, 0.663 mmol) in pyridine (8 mL) was added T₃P® (2111 mg,3.32 mmol) in portions. Then the mixture was stirred at 16° C. for 1 h.LCMS analysis showed the starting material disappeared. 10 mL of waterwas added dropwise into the reaction solution and then the mixture wasfiltered. The filter cake was washed with water (20 mL) and dried invacuo to afford pure product2-(4-(5-ethoxy-6-((4-methoxybenzypoxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide(200 mg, 0.263 mmol, 39.7% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.24 (s,1H), 8.06 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H),7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=9.0 Hz, 3H), 6.91 (d, J=8.8Hz, 2H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H),2.16 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).

Step 4:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

A solution of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide(160 mg, 0.252 mmol) in TFA (8 mL, 10.38 mmol) was stirred at 16° C. for1 h. LCMS analysis showed the starting material disappeared. The solventwas removed in vacuo. Then the crude material was purified bypreparative HPLC (Instrument: DB/Column: ASB C18 150*25 mm/Mobile phaseA: Water+0.1% HCl/Mobile phaseB: MeCN/Flowrate: 25 mL/min/GradientProfile Description: 53-83 (B %) to afford pure product2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride (15.92 mg, 0.029 mmol, 11.46% yield). ¹H NMR (400 MHz,MeOD-d₄): δ 8.22 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.57(s, 1H), 7.49-7.41 (m, 1H), 7.39-7.35 (m, 3H), 7.30 (d, J=2.0 Hz, 1H),4.16-4.12 (m, 2H), 3.84 (s, 2H), 2.16 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).ES-LCMS: m/z 515.2 (M+H).

Example 352-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

Step 1: 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole

To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg,2.391 mmol) and K₂CO₃ (496 mg, 3.59 mmol) in DMF (10 mL) was added3-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then themixture stirred under N₂ was heated to 110° C. and reacted for 15 h.LCMS analysis showed the starting material disappeared. The solvent wasremoved in vacuo and the residue obtained was dissolved in DCM (40 mL)and washed with H₂O (15 mL) and brine (15 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated to give a residue which waspurified by silica column chromatography (PE/EA=8/1 to 3/1) to affordpure product 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole(300 mg, 1.007 mmol, 42.1% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.84 (s,1H), 8.47 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 6.42 (d, J=2.4Hz, 1H), 2.36 (s, 3H). ES-LCMS: m/z 272.0 (M+H).

Step 2: 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline

To a solution of3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg,1.106 mmol) in MeOH (10 mL) was added Pd/C (11.77 mg, 0.111 mmol) in oneportion. Then the mixture was stirred under H₂ for 12 h. LCMS analysisshowed the starting material disappeared. The suspension was filteredthrough a pad of Celite® and the filter cake was washed with MeOH (2mL). The combined filtrates were concentrated to dryness to give crudeproduct which was purified by preparative TLC (PE/EA=5/1, R_(f)=0.35) toafford pure product3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (300 mg, 1.045mmol, 94% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.05 (d, J=2.4 Hz, 1H),7.18-7.12 (m, 2H), 6.82 (s, 1H), 6.30 (d, J=2.2 Hz, 1H), 2.32 (s, 3H).ES-LCMS: m/z 242.1 (M+H).

Step 3:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide

To a solution of 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline(250 mg, 1.036 mmol) and2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (429 mg, 1.036 mmol) in pyridine (5 mL) was added T₃P® (3298 mg,5.18 mmol) in portions. The mixture was stirred at 16° C. for 1 h. LCMSanalysis showed the starting material disappeared. 10 mL of water wasadded dropwise into the reaction solution and then the mixture wasfiltered. The filter cake was washed with water (20 mL) and dried invacuo to afford pure product2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide(280 mg, 0.357 mmol, 34.5% yield). ¹H NMR (400 MHz, CD₃OD): δ 8.25 (s,1H), 8.15 (d, J=2.6 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.75(s, 1H), 7.50-7.43 (m, 3H), 7.41 (d, J=9.0 Hz, 3H), 6.92 (d, J=8.8 Hz,2H), 6.36 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s,2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z635.1 (M+H).

Step 4:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

A solution of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide(220 mg, 0.347 mmol) in TFA (8 mL, 10.38 mmol) was stirred at 16° C. for1 h. LCMS analysis showed the starting material disappeared. The solventwas removed in vacuo. Then the crude material was purified bypreparative HPLC (Instrument: DB/Column: ASB C18 150*25 mm/Mobile phaseA: Water+0.1% HCl/Mobile phaseB: MeCN/Flowrate: 25 mL/min/GradientProfile Description: 53-83 (B %) to afford pure product2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride (113 mg, 0.197 mmol, 56.8% yield). ¹H NMR (400 MHz,MeOD-d₄): δ 8.24 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.85 (s, 1H), 7.74 (s,1H), 7.50-7.44 (m, 2H), 7.43-7.37 (m, 3H), 6.36 (d, J=2.2 Hz, 1H),4.21-4.16 (m, 2H), 3.85 (s, 2H), 2.34 (s, 3H), 1.48 (t, J=6.8 Hz, 3H).ES-LCMS: m/z 515.2 (M+H).

Example 36N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

Step 1:3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline

To a mixture of 3-bromo-5-(trifluoromethyl)aniline (1 g, 4.17 mmol) in1,4-dioxane (12 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.164 g,4.58 mmol), PdCl₂(dppf) (0.305 g, 0.417 mmol) and Cs₂CO₃ (2.71 g, 8.33mmol). The mixture was stirred at 100° C. for 2 h under N₂. The mixturewas filtered and concentrated, which was purified by silica columnchromatography (PE/EA=5:1). All fractions found to contain product byTLC (PE/EA=2:1, R_(f)=0.8) were combined and concentrated to yield alight yellow solid of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline(800 mg, 2.369 mmol, 56.9% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.27 (s,1H), 7.23 (s, 1H), 7.03 (s, 1H), 1.37 (s, 12H). ES-LCMS m/z 287.9 (M+H).

Step 2: tert-butyl 4-bromo-1H-pyrazole-1-carboxylate

To a mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol) in DCM (10 mL)was added Boc₂O (0.790 mL, 3.40 mmol) and Et₃N (0.948 mL, 6.80 mmol).The mixture was stirred at 25° C. for 1 h. The mixture was concentratedto afford tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (800 mg, 2.91mmol, 86% yield). TLC (PE/EA=2:1, R_(f)=0.6): ¹H NMR (400 MHz, CD₃OD) δ8.31 (s, 1H), 7.77 (s, 1H), 1.63 (s, 9H). ES-LCMS m/z 148.0 (M-Boc+H).

Step 3: 3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline

To a mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline(500 mg, 1.742 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was addedtert-butyl 4-bromo-1H-pyrazole-1-carboxylate (473 mg, 1.916 mmol),PdCl₂(dppf) (127 mg, 0.174 mmol) and Cs₂CO₃ (1135 mg, 3.48 mmol). Themixture was stirred at 100° C. for 16 h under N₂. The mixture wasfiltered and concentrated, which was purified by silica columnchromatography (PE/EA=1:1). All fractions found to contain product byTLC (PE/EA=1:1, R_(f)=0.2) were combined and concentrated. Then theresidue was purified by preparative TLC (DCM/MeOH=15:1, R_(f)=0.6) toyield a yellow solid of 3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline(8 mg, 0.030 mmol, 1.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s., 2H),7.08 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H). ES-LCMS m/z 228.1 (M+H).

Step 4:N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (15 mg, 0.036 mmol) in pyridine (3 mL) were added3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (8.28 mg, 0.036 mmol) andT₃P® (EA solvate) (0.5 mL, 0.036 mmol). The mixture was stirred at 25°C. for 1 h. The mixture was added to water and concentrated to affordN-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(50 mg, 0.024 mmol, 66.3% yield). TLC (DCM/MeOH=15:1, R_(f)=0.5): ¹H NMR(400 MHz, CD₃OD) δ 8.02 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.37 (s,2H), 7.32-7.30 (m, 4H), 7.25-7.23 (m, 2H), 6.89-6.86 (m, 3H), 5.36 (s,2H), 4.15-4.09 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.46 (t, J=6.8 Hz,3H). ES-LCMS m/z 621.2 (M+H).

Step 5:N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride

To a mixture ofN-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(50 mg, 0.081 mmol) in DCM (10 mL) was added TFA (1 mL, 12.98 mmol). Themixture was stirred at 25° C. for 2 h. The mixture was concentrated andNH₄OH (0.5 mL) was added. Then the reaction residue was concentrated andpurified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A:Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mL/min; GradientProfile Description: 40-70 (B %)) to yield an off-white solid ofN-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidehydrochloride (6.95 mg, 0.013 mmol, 15.9% yield): ¹H NMR (400 MHz,CD₃OD) δ 8.16 (s, 2H), 8.06 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H),7.48-7.42 (m, 1H), 7.41-7.34 (m, 3H), 7.33 (s, 1H), 4.15 (q, J=7.2 Hz,2H), 3.84 (s, 2H), 1.46 (t, J=7.2 Hz, 3H). ES-LCMS m/z 501.2 (M+H). TLC(DCM/MeOH=10:1, R_(f)=0.2)

Example 372-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamidehydrochloride

Step 1:(1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one

To a mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (10 g, 64.1mmol) in CHCl₃ (100 mL) cooled to 0° C. was added oxalyl chloride (7.29mL, 83 mmol) dropwise. The mixture was stirred at 70° C. for 4 h. Thenthe mixture was concentrated. To a mixture of(E)-4-methoxybut-3-en-2-one (12.83 g, 128 mmol) in THF (100 mL) cooledto −78° C. was added LiHMDS (128 mL, 128 mmol) dropwise under N₂. Themixture was stirred at −78° C. for 1 h. Then to the mixture was added asolution of 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride in THF (100mL) at −78° C. The whole mixture was allowed to warm to rt over 2 h andquenched by NH₄Cl (saturated aqueous, 30 mL). THF was removed undervacuum. To the mixture was added H₂O (80 mL) and then extracted with EA(100 mL×3). The organic layer was washed with brine (80 mL), dried overNa₂SO₄, filtered and concentrated. The crude material was purified bysilica column chromatography (PE/EA=2:1). All fractions found to containproduct by TLC (PE/EA=2:1, R_(f)=0.5) were combined to yield anoff-white oil of(1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one(1 g, 3.36 mmol, 5.2% yield): ¹H NMR (400 MHz, CDCl₃): δ 15.90 (s, 1H),7.65 (d, J=12.4 Hz, 1H), 5.63 (s, 1H), 5.33 (d, J=12.4 Hz, 1H), 3.74 (s,3H), 1.38 (s, 6H). ES-LCMS m/z 239.1 (M+H).

Step 2: 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one

To a mixture of(1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one(1 g, 4.20 mmol) in toluene (5 mL) was added TFA (0.647 mL, 8.40 mmol).The mixture was stirred at 25° C. for 16 h. Then the mixture wasconcentrated to afford2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800 mg, 3.10mmol, 73.9% yield). TLC (PE/EA=1:1, R_(f)=0.2): ¹H NMR (400 MHz, CD₃OD):δ 8.12 (d, J=6.0 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.39 (dd, J=2.4, 6.0Hz, 1H), 1.53 (s, 6H). ES-LCMS m/z 207.1 (M+H).

Step 3: 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one

A mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800mg, 3.88 mmol) in NH₄OH (8 mL, 205 mmol) was stirred at 90° C. for 1 h.Then the mixture was concentrated, triturated with MeOH (20 mL) andfiltered. The filtrate was concentrated and purified by silica columnchromatography (DCM/MeOH=9:1). All fractions found to contain product byTLC (DCM/MeOH=9:1, R_(f)=0.2) were combined and concentrated to yield ayellow oil of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one(700 mg, 2.90 mmol, 74.7% yield): ¹H NMR (400 MHz, CD₃OD): δ 7.87 (d,J=7.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.54 (dd, J=2.4, 7.2 Hz, 1H),1.60 (s, 6H). ES-LCMS m/z 206.1 (M+H).

Step 4: 5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one

To a mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one(300 mg, 1.462 mmol) in H₂SO₄ (8 mL, 150 mmol) was added nitric acid(3.27 mL, 73.1 mmol). The mixture was stirred at 90° C. for 15 h. Thenthe mixture was added to ice water and basified by aqueous NaOHsolution. The mixture was filtered. The filtrate was concentrated andpurified by preparative TLC (DCM/MeOH=9:1, R_(f)=0.1) to yield a lightyellow solid of5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (100mg, 0.380 mmol, 26.0% yield): ¹H NMR (400 MHz, CD₃OD): δ 8.82 (s, 1H),6.95 (s, 1H), 1.64 (s, 6H). ES-LCMS m/z 251.1 (M+H).

Step 5: 4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine

To a mixture of5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (100mg, 0.400 mmol) in DCE (10 mL) was added phosphoryl tribromide (138 mg,0.480 mmol). The mixture was stirred at 85° C. for 1 h. Then the mixturewas added to aqueous NaHCO₃ solution. The mixture was extracted with EA(50 mL×2). The combined organic extracts were washed with brine, driedover MgSO₄, filtered and concentrated to afford4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (60 mg,0.096 mmol, 24.0% yield). TLC (PE/EA=10:1, R_(f)=0.6): ¹H NMR (400 MHz,CD₃OD): δ 8.74 (s, 1H), 6.83 (s, 1H), 1.54 (s, 6H). ES-LCMS m/z 312.9(M+H).

Step 6: 4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine

To a mixture of4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (50 mg,0.160 mmol) in EtOH (10 mL) was added tin(II) chloride dihydrate (180mg, 0.799 mmol). The mixture was stirred at 85° C. for 16 h. Then themixture was added to an aqueous NaHCO₃ solution. The mixture wasextracted with EA (50 mL×2). The combined organic extracts were washedwith brine, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by preparative TLC (PE/EA=2:1, R_(f)=0.5) to yielda light yellow solid of4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (30 mg,0.090 mmol, 56.4% yield): ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.58(s, 1H), 1.56 (s, 6H). ES-LCMS m/z 283.1 (M+H).

Step 7:N-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (30 mg, 0.073 mmol) in pyridine (5 mL) was added4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (20.64mg, 0.073 mmol) and T₃P® (EA solvate) (0.5 mL, 0.073 mmol). The mixturewas stirred at 25° C. for 1 h. The mixture was concentrated and purifiedby preparative TLC (DCM/MeOH=15:1, R_(f)=0.6) to yield a light yellowsolid ofN-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(30 mg, 0.038 mmol, 51.7% yield): ¹H NMR (400 MHz, CD₃OD): δ 8.84 (s,1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.33 (d, J=9.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.48 (s, 1H),5.30 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 3.93 (s, 2H), 3.82 (s, 3H), 1.63(s, 6H), 1.40 (t, J=7.0 Hz, 3H). ES-LCMS m/z 678.0 (M+H+2).

Step 8:2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamidehydrochloride

To a mixture ofN-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(30 mg, 0.044 mmol) in DCM (10 mL) was added Pd/C (4 mg, 0.038 mmol).The mixture was stirred at 25° C. for 72 h under H₂. The mixture wasfiltered and concentrated. The crude material was purified bypreparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1%HCl; Mobile phaseB: MeCN; Flowrate: 25 mL/min; Gradient ProfileDescription: 45-75 (B %)) to yield an off-white solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamidehydrochloride (7.91 mg, 0.015 mmol, 34.6% yield). TLC (DCM/MeOH=9:1,R_(f)=0.2): ¹H NMR (400 MHz, CD₃OD): δ 9.08 (d, J=2.0 Hz, 1H), 8.32 (dd,J=2.4, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.44 (t, J=8.0Hz, 1H), 7.34-7.27 (m, 2H), 6.39 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.89(s, 2H), 1.69 (s, 6H), 1.41 (t, J=7.2 Hz, 3H). ES-LCMS m/z 478.1 (M+H).

Example 38N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Stepl:N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)-pyridin-3-yl)-2-fluorophenyl)acetamide

To a solution of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (1 g, 2.431 mmol) and 4-amino-2-(trifluoromethyl)benzonitrile(0.452 g, 2.431 mmol) in pyridine (3.93 mL, 48.6 mmol) was added T₃P®(4.64 g, 7.29 mmol) slowly. The mixture was stirred at rt for 0.5 h. Thereaction was quenched with H₂O (10 mL) and extracted with DCM (20 mL×5).The combined organic extracts were dried, filtered, and concentrated.Purification by column chromatography (PE/EA=511, R_(f)=0.6) providedN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(870 mg, 1.351 mmol, 55.6% yield). ¹H NMR (400 MHz, CDCl₃-d): δ 8.02 (s,1H), 7.98 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H),7.30-7.45 (m, 5H), 6.93 (d, J=8 Hz, 2H), 6.33 (s, 1H), 5.33 (d, J=8 Hz,2H), 4.09 (q, J=6.8 Hz, 2H), 3.83 (s, 5H), 1.41 (t, J=6.8 Hz, 3H); LCMS(m/z): 580.0 (M+H).

Step 2:N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

To a solution ofN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)acetamide(870 mg, 1.501 mmol) in DCM (10 mL) was added TFA (1.157 mL, 15.01 mmol)at 0° C. The mixture was stirred at rt for 1 h. The mixture was basifiedwith NH₄OH (5 mL, 20%) to pH=8, filtered to give a solid, which waswashed with H₂O (5 mL) and dried to afford the productN-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(462.91 mg, 0.973 mmol, 64.8% yield): ¹H NMR (400 MHz, CD₃OD): δ 8.24(s, 1H), 7.96-8.05 (m, 1H), 7.90-7.96 (m, 1H), 7.36-7.40 (m, 2H),7.20-7.28 (m, 2H), 6.00 (s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.85 (s, 2H),1.38 (t, J=7.2 Hz, 3H): LCMS (m/z): 459.9 (M+H).

Example 392-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide

Step 1: 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine

A mixture of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (800 mg, 3.83mmol), 2-morpholinoethanol (552 mg, 4.21 mmol) and K₂CO₃ (1586 mg, 11.48mmol) in DMF (20 mL) was stirred at 90° C. for 10 h. The mixture wasconcentrated. To the residue was added DCM (150 mL) and the mixture wasstirred for 10 min and then filtered. The filtrate was concentrated. Theresidue was purified by silica column chromatography (PE/EA=10:1-5:1).All fractions found to contain product by TLC (PE/EA=5:1, R_(f)=0.6)were combined and concentrated to yield a yellow solid of4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.780mmol, 46.5% yield): ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 1H), 7.87 (s,1H), 7.43 (s, 1H), 4.16 (t, J=5.6 Hz, 2H), 3.72-3.63 (m, 4H), 2.79 (t,J=5.6 Hz, 2H), 2.58-2.47 (m, 4H). ES-LCMS m/z: 321 (M+H).

Step 2: 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline

To a mixture of4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.873mmol) in MeOH (50 mL) was added Pd/C (19.94 mg, 0.187 mmol) under N₂.The mixture was stirred under H₂ at 25° C. for 5 h. The mixture wasfiltered, and the filtrate was concentrated to give a yellow oil of3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (500 mg, 1.490 mmol,80% yield): ¹H NMR (400 MHz, CDCl₃): δ 6.52 (d, J=9.2 Hz, 2H), 6.35 (s,1H), 4.12-4.02 (m, 2H), 3.82 (s, 2H), 3.76-3.66 (m, 4H), 2.78 (t, J=5.6Hz, 2H), 2.57 (d, J=4.0 Hz, 4H). ES-LCMS m/z: 291 (M+H).

Step 3:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholino-ethoxy)-5-(trifluoromethyl)phenyl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (70.9 mg, 0.172 mmol) and3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (50 mg, 0.172 mmol) inpyridine (5 mL) was added T₃P® (50% in EA, 0.3 mL) dropwise and themixture was stirred at 25° C. for 1 h. The mixture was quenched withcold water (20 mL), extracted with DCM/MeOH (10:1, v/v, 20 mL×3). Theorganic layer was dried over Na₂SO₄ and concentrated to give an offwhite solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide(80 mg, 0.111 mmol, 64.5% yield): ¹H NMR (400 MHz, CD₃OD): δ 7.94 (d,J=1.8 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.45-7.35 (m, 6H), 6.95-6.88(m, 3H), 5.35 (s, 2H), 4.20-4.10 (m, 4H), 3.80 (s, 2H), 3.78 (s, 3H),3.73-3.66 (m, 4H), 2.81 (t, J=5.4 Hz, 2H), 2.59 (d, J=4.2 Hz, 4H), 1.41(t, J=6.8 Hz, 3H). ES-LCMS m/z: 684 (M+H).

Step 4:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide

A mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide(80 mg, 0.117 mmol) and TFA (10 mL, 10% in DCM) was stirred at 25° C.for 2 h. The mixture was concentrated. To the residue was added NH₃ (6mol/L in MeOH, 1 mL) and concentrated. The residue was purified bypreparative TLC (DCM/MeOH=15:1, R_(f)=0.4) to give an off white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide(35.72 mg, 0.061 mmol, 51.7% yield): ¹H NMR (400 MHz, CD₃OD): δ 7.59 (s,1H), 7.46 (s, 1H), 7.43-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.29 (d, J=2.0Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.96 (s, 1H), 4.23 (t, J=5.2 Hz, 2H),4.11 (q, J=6.8 Hz, 2H), 3.79 (s, 2H), 3.78-3.69 (m, 4H), 3.02-3.00 (m,2H), 2.80-2.79 (m, 4H), 1.45 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 564 (M+H).

Example 402-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

Step 1:2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a mixture of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (1.060 g, 2.58 mmol) and3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.5 g, 2.58mmol) in pyridine (20 mL) was added T₃P® (50% in EA, 5 mL, 2.58 mmol)dropwise and stirred at 25° C. for 1 h. The mixture was poured intostirring cold water (100 mL). The mixture was stirred for 0.5 h and leftstanding for 10 h. The resulting solid was filtered, washed with H₂O(200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off whitesolid2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(1.5 g, 2.298 mmol, 89% yield): ¹H NMR (400 MHz, CD₃OD): δ 7.96 (s, 1H),7.40-7.32 (m, 3H), 7.28 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.45(s, 1H), 6.38 (s, 1H), 5.27 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.83 (s,2H), 3.79 (s, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z:588 (M+H).

Step 2:2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

To a suspension of2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(1.5 g, 2.55 mmol) in DCM (20 mL) was added TFA (2 mL, 26.9 mmol)dropwise. The mixture was stirred at 25° C. for 2 h. The mixture wasthen concentrated. To the residue was added H₂O (50 mL) dropwise andthen neutralized with saturated Na₂CO₃ solution to adjust pH=7.5. Theprecipitate was filtered, washed with H₂O (50 mL×3) and dried in vacuo.To the solid was added PE/EA (3:1, v/v, 30 mL) and stirred for 0.5 h.The solid was filtered, washed with PE/EA (3:1, v/v, 30 mL×2). The solidwas redissolved in DCM/MeOH (20:1, v/v, 50 mL) and then concentrated invacuo to a minimal amount of solvent (about 10 mL). The solid wasfiltered, washed with CH₃CN (10 mL×2) and dried in vacuo. The residuewas redissolved in DCM/MeOH (10:1, v/v, 50 mL) and concentrated in vacuoto give a white solid of2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide(440 mg, 0.938 mmol, 36.7% yield): ¹H NMR (400 MHz, CD₃OD): δ 7.39-7.36(m, 1H), 7.36-7.30 (m, 1H), 7.25-7.18 (m, 2H), 6.37 (s, 1H), 5.99 (s,1H), 4.11 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=6.8Hz, 3H). ES-LCMS m/z: 468 (M+H); CHN analytical report: average(%): N,8.717; C, 55.32; H, 4.672.

Example 412-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride

Step 1: 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile

To a mixture of acetonitrile (3.22 g, 44.1 mmol) in THF (60 mL) at −78°C. was added n-BuLi (17.63 mL, 44.1 mmol). The mixture was stirred at−30° C. for 0.5 h. Then to the mixture was added methyl3,3,3-trifluoro-2,2-dimethylpropanoate (5 g, 29.4 mmol) dropwise. Thenthe mixture was stirred for another 1 h. The mixture was quenched withsaturated NH₄Cl solution (50 mL), and extracted with EA (100 mL×2). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to yielda yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g,16.75 mmol, 57.0% yield): ¹H NMR (400 MHz, CD₃OD): δ 3.75 (s, 2H), 1.40(s, 6H).

Step 2:1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine

To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g,5.58 mmol) in EtOH (10 mL) was added methylhydrazine (3.33 g, 28.9 mmol)and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C.for 18 h. Then the mixture was concentrated to give the residue whichwas distributed between DCM (20 mL) and H₂O (10 mL) and extracted withDCM (20 mL×2). The combined organic extracts were washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by silica column chromatography (40% EA: 60% PE, 12 g silicacolumn). All fractions found to contain product by TLC (EA:PE=1:2,R_(f)=0.2) were combined and concentrated to yield a white solid of1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500mg, 2.293 mmol, 41.1% yield): ¹H NMR (400 MHz, CD₃OD): δ 5.48 (s, 1H),3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H).

Step 3:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (150 mg, 0.365 mmol),1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (83mg, 0.401 mmol) in pyridine (3 mL) was added T₃P® (EA solvate) (0.3 mL,0.365 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixturewas concentrated to give the residue which was distributed between DCM(20 mL) and H₂O (10 mL) and extracted with DCM (20 mL×2). The combinedorganic extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to yield a white solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide(150 mg, 0.225 mmol, 61.7% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d,J=4.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.44-7.41 (m, 3H), 7.39 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.27 (s, 1H), 5.35 (s, 2H), 4.13 (q,J=7.1 Hz, 2H), 3.83 (s, 2H), 3.78 (s, 3H), 3.72-3.67 (m, 3H), 1.47 (s,6H), 1.41 (t, J=7.0 Hz, 3H). ES-LCMS m/z 601 (M+H).

Step 4:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride

A mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide(150 mg, 0.250 mmol) in TFA.DCM (solvate) (10 mL, 10%) was stirred for0.5 h at 25° C. Then the mixture was concentrated to give the residuewhich purified by preparative HPLC (column: ASB C18 150*25 mm/Mobilephase A: Water (Water+0.1% HCl)/Mobile phaseB: Acetonitrile/Gradient:37-67(B %)/Flowrate: 25 mL/min/Run time: 15 min) to yield2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride (83.1 mg, 0.160 mmol, 63.9% yield): ¹H NMR (400 MHz,CD₃OD) δ 7.48-7.41 (m, 1H), 7.39 (s, 1H), 7.37 (d, J=3.5 Hz, 1H), 7.33(d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 6.29 (s, 1H), 4.15 (q, J=7.0Hz, 2H), 3.86 (s, 2H), 3.73 (s, 3H), 1.51 (s, 6H), 1.50-1.45 (m, 3H).ES-LCMS m/z 481 (M+H).

Example 422-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride

Step 1: 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile

To a mixture of acetonitrile (3.22 g, 44.1 mmol) in THF (60 mL) at −78°C. was added n-BuLi (17.63 mL, 44.1 mmol, 2.5 mol/L). The mixture wasstirred at −30° C. for 0.5 h. Then to the mixture was added methyl3,3,3-trifluoro-2,2-dimethylpropanoate (5 g, 29.4 mmol) dropwise. Thenthe mixture was stirred for another 1 h. The mixture was quenched withsaturated NH₄Cl solution (50 mL), extracted with EA (100 mL×2). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to yielda crude product as a yellow oil of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g, 16.75 mmol, 57.0%yield): ¹H NMR (400 MHz, CD₃OD) δ 3.75 (s, 2H), 1.40 (s., 6H).

Step 2: 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine

To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (2 g,11.16 mmol) in EtOH (10 mL) was added hydrazine (1.263 g, 33.5 mmol) andconcentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for18 h. Then the mixture was concentrated to give the residue which wasdistributed between DCM (20 mL) and H₂O (10 mL), and extracted with DCM(20 mL×2). The combined organic extracts were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by silica column chromatography (100% EA, 12 g silica column).All fractions found to contain product by TLC (EA, R_(f)=0.3) werecombined and concentrated to yield an off-white oil of3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg,2.459 mmol, 22.03% yield): ¹H NMR (400 MHz, CD₃OD) δ 5.58 (s, 1H), 1.47(s, 6H). ES-LCMS m/z 194 (M+H).

Step 3:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (100 mg, 0.243 mmol) and3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (51.6 mg,0.267 mmol) in pyridine (3 mL) was added T₃P® (EA solvate) (0.3 mL,0.243 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixturewas concentrated to give a residue which was distributed between DCM (20mL) and H₂O (10 mL) and extracted with DCM (20 mL×2). The combinedorganic extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to yield a white solid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide(100 mg, 0.102 mmol, 42.1% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d,J=4.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.48-7.33 (m, 6H), 6.90 (d, J=8.6Hz, 2H), 5.35 (s, 2H), 4.19-4.09 (m, 2H), 3.78 (s, 3H), 3.70-3.63 (m,2H), 1.54-1.36 (m, 9H). ES-LCMS m/z 587 (M+H).

Step 4:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride

A mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide(100 mg, 0.170 mmol) in TFA.DCM (solvate) (10 mL, 10%) was stirred for0.5 h at 25° C. Then the mixture was concentrated to give a residuewhich purified by preparative HPLC (column: ASB C18 150*25 mm/Mobilephase A: Water(Water+0.1% HCl)/Mobile phaseB: Acetonitrile/Gradient:33-63 (B %)/Flowrate: 25 mL/min/Run time: 15 min) to yield a white solidof2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamidehydrochloride (43.33 mg, 0.084 mmol, 49.2% yield): NMR (400 MHz,DMSO-d6) δ 11.81 (s, 1H), 10.68 (s, 1H), 7.46-7.28 (m, 5H), 7.11 (d,J=2.0 Hz, 1H), 6.41 (s, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.45(s, 6H), 1.32 (t, J=6.9 Hz, 3H). ES-LCMS m/z 467 (M+H).

Example 43N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: Ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate

To a mixture of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.5 g, 2.092mmol) in DMSO (10 mL) was added ethyl 2,2-difluoro-2-iodoacetate (0.410mL, 2.000 mmol) and copper (0.439 g, 6.90 mmol) at rt. The mixture wasstirred at 20° C. for 10 h. The mixture was extracted with EA, washedwith brine, and the organic layer was concentrated to give ethyl2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate (320 mg, 0.981mmol, 46.9% yield): ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.72 (d, J=7.8 Hz, 1H),7.60-7.45 (m, 3H), 4.26 (d, J=7.1 Hz, 2H), 3.63 (t, J=16.9 Hz, 2H), 1.24(t, J=7.2 Hz, 3H).

Step 2: 2,2-Difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate

A mixture of ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate(250 mg, 0.886 mmol) in H₂SO₄ (5 mL) was added potassium nitroperoxousacid (99 mg, 0.974 mmol) at rt. The mixture was stirred at 20° C. for 2h. TLC (PE/EA=5:1, R_(f)=0.6) showed the reaction was finished. Themixture was poured into ice-water. The mixture was extracted with EA (10mL×3) and washed with water. The organic layer was concentrated to giveethyl 2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (230mg, 0.643 mmol, 72.6% yield): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.56 (d,J=2.2 Hz, 1H), 8.48 (dd, J=2.4, 8.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H),4.31 (q, J=7.1 Hz, 2H), 3.80 (t, J=17.0 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

Step 3: Ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate

To a mixture of ethyl2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (220 mg,0.672 mmol) in MeOH (10 mL) was added Pd/C (71.6 mg, 0.672 mmol) underN₂. The mixture was then stirred under a H₂ atmosphere for 1 h. LCMS andTLC (PE/EA=5:1, R_(f)=0.3) showed the reaction was finished. The mixturewas filtered and the filtrate was concentrated to give ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (190 mg,0.573 mmol, 85% yield): NMR (400 MHz, CD₃OD-d₄) δ 7.15 (s, 1H), 6.97 (d,J=2.2 Hz, 1H), 6.81 (dd, J=2.1, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H),3.42 (t, J=16.8 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H). ES-LCMS m/z 298 (M+H).

Step 4: Ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (150 mg, 0.365 mmol) in pyridine (2 mL) were added ethyl3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (108 mg,0.365 mmol) and T₃P® (EA solvate) (464 mg, 0.729 mmol). The mixture wasstirred at 20° C. for 1 h. LCMS and TLC (PE/EA=1:1, R_(f)=0.5) showedthe reaction was finished. The mixture was concentrated and thenpurified by TLC (PE/EA=1:1, R_(f)=0.5) to give ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate(120 mg, 0.150 mmol, 41.2% yield): ¹H NMR (400 MHz, CD₃OD-d₄) δ8.08-8.02 (m, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.54-7.33 (m,7H), 6.90 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.13(q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 3.63-3.52 (m, 2H), 1.41(t, J=7.1 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); ES-LCMS m/z 691 (M+H).

Step 5:N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of ethyl3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate(100 mg, 0.145 mmol) in THF (5 mL) was added LAH (5.50 mg, 0.145 mmol)at 0° C. The mixture was stirred for 1 h. LCMS and TLC (PE/EA=1:1,R_(f)=0.2) showed the reaction was finished. The reaction was quenchedby water (0.3 mL). The mixture was filtered, and the filtrate wasconcentrated to giveN-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(80 mg, 0.104 mmol, 71.6% yield):

¹H NMR (400 MHz, CD₃OD-d₄) δ 8.01 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.77(d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.47-7.27 (m, 6H), 6.90 (d,J=8.8 Hz, 2H), 5.35 (s, 2H), 4.22-4.11 (m, 2H), 3.82-3.75 (m, 3H), 3.67(t, J=13.0 Hz, 2H), 3.47-3.37 (m, 2H), 3.37-3.34 (m, 2H), 1.41 (t, J=7.1Hz, 3H). ES-LCMS m/z 649 (M+H).

Step 6:N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

A mixture ofN-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(50 mg, 0.077 mmol) in DCM (5 mL) was added TFA (0.012 mL, 0.154 mmol).The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction wasfinished. The mixture was concentrated to give crude product, which waspurified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A:Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25mLl/min; GradientProfile Description: 26-56 (B %)) to giveN-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(16.72 mg, 0.032 mmol, 41.0% yield): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.01(s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.5Hz, 1H), 7.36-7.26 (m, 3H), 7.23 (s, 1H), 4.12 (d, J=7.1 Hz, 2H), 3.80(s, 2H), 3.68 (t, J=12.8 Hz, 2H), 3.41 (t, J=17.1 Hz, 2H), 1.45 (t,J=6.9 Hz, 3H). ES-LCMS m/z 529(M+H).

Example 44N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 3-nitro-5-(trifluoromethyl)benzoyl chloride

A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (2 g, 8.51 mmol) inDCM (30 mL) was added SOCl₂ (1.242 mL, 17.01 mmol) at 20° C. The mixturewas stirred at 20° C. for 2 h. TLC (PE/EA=2:1, R_(f)=0.3) showed thereaction was finished. The mixture was concentrated to give3-nitro-5-(trifluoromethyl)benzoyl chloride (1.8 g, 6.50 mmol, 76%yield).

Step 2: 3-Nitro-5-(trifluoromethyl)benzamide

To a mixture of 3-nitro-5-(trifluoromethyl)benzoyl chloride (1.8 g, 7.10mmol) in THF (20 mL) was added NH₄OH (2.96 mL, 21.30 mmol) at 20° C. Themixture was stirred at 20° C. for 12 h. LCMS showed the reaction wasfinished. The mixture was extracted with EA, washed with water, andconcentrated to give 3-nitro-5-(trifluoromethyl)benzamide (1.5 g, 5.86mmol, 83% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.62 (br.s,2H), 8.53 (s, 1H), 7.93 (s., 1H). ES-LCMS m/z 235 (M+H).

Step 3: 3-Nitro-5-(trifluoromethyl)benzonitrile

To a mixture of 3-nitro-5-(trifluoromethyl)benzamide (1.5 g, 6.41 mmol)in DCM (20 mL) were added Et₃N (1.314 mL, 9.61 mmol) and trifluoroaceticanhydride (1.357 mL, 9.61 mmol) at 20° C.

The mixture was stirred at 20° C. for 2 h. TLC (PE/EA=3:1, R_(f)=0.6)showed the reaction was finished. The reaction was concentrated to givecrude product, which was purified by column chromatography (PE/EA=3:1,R_(f)=0.6) to give 3-nitro-5-(trifluoromethyl)benzonitrile (1.2 g, 5.14mmol, 80% yield): ¹H NMR (400 MHz, CDCl₃-d) δ 8.71 (s, 2H), 8.24 (s,1H).

Step 4: 5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole

To a mixture of 3-nitro-5-(trifluoromethyl)benzonitrile (400 mg, 1.851mmol) in DMF (20 mL) was added sodium azide (361 mg, 5.55 mmol) at rt.The mixture was stirred at 120° C. overnight. LCMS showed the reactionwas finished. The reaction was quenched by water. The mixture wasextracted with EA (20 mL×3), washed with water, and concentrated to give5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole (220 mg, 0.743 mmol,40.1% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.73 (s, 1H),8.66 (s, 1H), 7.92 (s, 1H). ES-LCMS m/z 260 (M+H).

Step 5: 3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline

A mixture of 5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole (220 mg,0.849 mmol) in MeOH (10 mL) was added Pd/C (45.2 mg, 0.424 mmol) underN₂. The mixture was stirred at 20° C. under a H₂ atmosphere for 1 h.LCMS showed the reaction was finished. The mixture was filtrated, andthe filtrate was concentrated to give3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (200 mg, 0.781 mmol, 92%yield): ¹H NMR (400 MHz, METHANOL-d₄) δ 7.96 (s, 1H), 7.71 (s, 1H), 7.32(s, 1H). ES-LCMS (m/z) 230 (M+H).

Step 6:N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) in pyridine (10 mL) were added3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (55.7 mg, 0.243 mmol)and T₃P® (EA solvate) (220 mg, 0.346 mmol). The mixture was stirred at20° C. for 1 h. LCMS showed the reaction was finished. The reaction wasquenched with ice-water. The mixture was concentrated to give crudeproduct, which was purified by TLC to giveN-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (75 mg, 0.104 mmol, 42.9% yield):

¹H NMR (400 MHz, CD₃OD-d₄) δ 8.62 (d, J=4.4 Hz, 2H), 8.04 (d, J=1.5 Hz,1H), 7.94 (s, 1H), 7.61 (dd, J=6.1, 7.8 Hz, 2H), 7.38 (d, J=8.6 Hz, 3H),6.92-6.85 (m, 3H), 5.35 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 3.77 (s, 2H),3.38-3.33 (m, 3H), 1.30-1.18 (m, 3H). ES-LCMS m/z 623(M+H).

Step 7:N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

To a mixture ofN-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.048 mmol) in DCM (5mL) was added TFA (7.42 4, 0.096 mmol). The mixture was stirred at 20°C. for 1 h. LCMS showed the reaction was finished. The mixture wasconcentrated to give crude product, which was purified by preparativeHPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; MobilephaseB: MeCN; Flowrate: 25mLl/min; Gradient Profile Description: 30-66(B %)) to giveN-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(5.12 mg, 10.01 μmol, 20.8% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.83(br. s., 1H), 11.33 (s, 1H), 10.85 (s, 1H), 8.69-8.57 (m, 1H), 8.21 (s,1H), 8.01 (s, 1H), 7.47 (d, J=11.7 Hz, 1H), 7.42-7.27 (m, 3H), 7.12 (br.s., 1H), 4.03 (d, J=6.8 Hz, 2H), 3.79 (s, 2H), 1.31 (t, J=6.8 Hz, 3H).ES-LCMS m/z 503(M+H).

Example 452-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

Step 1:1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A suspension of 4-bromo-1-methyl-1H-pyrazole (2 g, 12.42 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.47 g,13.66 mmol), KOAc (2.438 g, 24.84 mmol), PdCl₂(dppf) (0.909 g, 1.242mmol) in 1,4-dioxane (20 mL) was heated to 100° C. for 5 h under N₂atmosphere. The mixture was concentrated to give the residue which wasextracted with DCM (15 mL×2). The organic extract was washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated, and then thecrude product was purified by silica column chromatography (10% EA: 90%Petroleum ether, 4 g silica column). All fractions found to containproduct by TLC (EA: Petroleum ether=1:1, R_(f)=0.3) were combined andconcentrated to yield a yellow solid of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(700 mg, 3.36 mmol, 27.1% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s,1H), 7.66 (s, 1H), 3.92 (s, 3H), 1.32 (s, 12H). ES-LCMS m/z 209 (M+H).

Step 2: 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole

A suspension of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (1 g, 3.70mmol) in 1,4-dioxane (12 mL) and water (4 mL) was added to a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.771 g, 3.70 mmol) in 1,4-dioxane (12 mL) and water (4 mL).PdCl₂(dppf) (0.271 g, 0.370 mmol) and Cs₂CO₃ (2.413 g, 7.41 mmol) wereadded and the mixture was heated at 100° C. for 20 min. The mixture wasthen cooled to rt. Then the solution was concentrated and distributedbetween EA and saturated NaHCO₃ solution. The combined organic extractswere washed with brine, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by silica column chromatography (PE/EA=1:1).All fractions found to contain product by TLC (PE/EA=5:1, R_(f)=0.3)were combined and concentrated to yield a light yellow solid of1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg,1.106 mmol, 29.9% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 8.31(s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 4.01 (s, 3H). ES-LCMSm/z 272 (M+H).

Step 3: 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline

To a suspension of1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg,1.106 mmol) in MeOH (10 mL) was added Pd/C (118 mg, 1.106 mmol). Themixture was hydrogenated at 40 psi at 28° C. for 12 h under a H₂atmosphere. Then the solution was filtered and concentrated to yield3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (240 mg, 0.995mmol, 90% yield). TLC (PE/EA=1:1, R_(f)=0.3): ¹H NMR (400 MHz, CD₃OD) δ7.98 (s, 1H), 7.81 (s, 1H), 7.16 (d, J=7.3 Hz, 2H), 6.88 (s, 1H), 3.92(s, 3H). ES-LCMS m/z 242 (M+H).

Step 4:2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide

To a solution of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (100 mg, 0.243 mmol) and3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (58.6 mg, 0.243mmol) in pyridine (2 mL) was added T₃P® (0.5 mL, 0.243 mmol) at 27° C.under N₂. The mixture was stirred at 27° C. for 30 min. LCMS showed thereaction was completed. Then the mixture was put onto ice (5 g). Themixture was concentrated to give the residue. The residue was purifiedby preparative TLC (DCM/MeOH=10:1, R_(f)=0.6) to yield a light yellowsolid of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide(138 mg, 0.217 mmol, 89% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.09-7.93 (m,2H), 7.87-7.76 (m, 2H), 7.69-7.52 (m, 2H), 7.49-7.33 (m, 4H), 7.23 (dd,J=7.8, 16.4 Hz, 2H), 6.91 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H),5.38-5.15 (m, 2H), 4.15 (d, J=7.1 Hz, 2H), 3.94-3.60 (m, 8H), 1.42 (t,J=6.8 Hz, 3H). ES-LCMS m/z 635 (M+H).

Step 5:2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride

A solution of TFA (10% in DCM, 10 mL) was added to a suspension of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-O-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide(138 mg, 0.217 mmol) in DCM (5 mL). The mixture was stirred at 26° C.for 3 h. Then the solution was concentrated between 40° C. and 45° C.The crude material was purified by preparative HPLC (Instrument:DC/Column: ASB C18 150*25 mm/Mobile phase A: Water+0.1% HCl/MobilephaseB: MeCN/Flowrate: 25 mL/min/Gradient Profile Description: 18-38 (B%)) to give an off-white solid of2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamidehydrochloride (31.5 mg, 0.057 mmol, 26.3% yield). TLC (DCM/MeOH=10:1,R_(f)=0.6): ¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 8.11-8.02 (m, 2H),7.84 (s, 1H), 7.73 (d, J=2.5 Hz, 2H), 7.60 (s, 1H), 7.55-7.43 (m, 3H),4.30 (q, J=6.7 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 2H), 1.51 (t, J=7.0 Hz,3H). ES-LCMS m/z 515 (M+H).

Example 46N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: N,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine

A suspension of 2-(dimethylamino)ethanol (128 mg, 1.435 mmol) in DMF (5mL) was added to a solution of1-fluoro-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.956 mmol) in DMF(5 mL). K₂CO₃ (264 mg, 1.913 mmol) was added and the mixture was stirredat 80° C. for 8 h. The mixture was cooled to rt. Then the solution wasconcentrated and distributed between ethyl acetate and saturated NaHCO₃solution. The combined organic extracts were washed with brine, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby preparative TLC (PE/EA=5:1, R_(f)=0.6) to yield a light yellow solidof N,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine (75 mg,0.270 mmol, 28.2% yield): ¹H NMR (400 MHz, CD₃OD) δ 8.22-8.02 (m, 2H),7.72 (s, 1H), 4.43 (t, J=5.1 Hz, 2H), 3.26 (t, J=4.9 Hz, 2H), 2.78-2.60(m, 6H). ES-LCMS m/z 279 (M+H).

Step 2: 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline

A suspension ofN,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine (75 mg,0.270 mmol) in MeOH (5 mL) was added to a solution of Pd/C (57.4 mg,0.539 mmol) in MeOH (5 mL). The mixture was hydrogenated at 26° C. for 3h under a H₂ atmosphere. Then the solution was filtered and concentratedto afford 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (60.3mg, 0.243 mmol, 90% yield). TLC (PE/EA=1:1, R_(f)=0.5): ¹H NMR (400 MHz,CD₃OD) δ 6.56 (s, 1H), 6.48 (s, 2H), 4.24-4.17 (m, 2H), 3.18 (t, J=5.1Hz, 2H), 2.67 (s, 6H). ES-LCMS m/z 249 (M+H).

Step 3:N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

To a solution of2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)aceticacid (100 mg, 0.243 mmol) and3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (60.3 mg, 0.243mmol) in pyridine (2 mL) was added T₃P® (0.5 mL, 0.243 mmol) at 27° C.under N₂. The mixture was stirred at 27° C. for 30 min. LCMS showed thereaction was completed. Then the mixture was put onto ice (10 mg). Theprecipitate was filtered and redissolved in DCM (5 mL). The solution waswashed with water (5 mL×2), and the combined organic extracts were driedover Na₂SO₄, filtered and concentrated. The residue was suspended inPE/EA (2:1, v/v, 8 mL) and stirred for 10 min. The solid was filtered,and washed with PE/EA (2:1, v/v, 10 mL) and dried in vacuo to give anoff-white solid ofN-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.156 mmol, 64.1% yield). TLC (PE/EA=1:1, R_(f)=0.3): ¹HNMR (400 MHz, CD₃OD) δ 7.97-7.92 (m, 1H), 7.76 (br. s., 1H), 7.48-7.37(m, 7H), 7.04 (s, 1H), 6.91 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.14 (q,J=7.1 Hz, 4H), 3.86-3.78 (m, 5H), 2.97 (br. s., 8H), 1.42 (t, J=6.9 Hz,4H). ES-LCMS m/z 642 (M+H).

Step 4:N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

To a suspension ofN-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide(100 mg, 0.156 mmol) in MeOH (10 mL) was added Pd/C (16.59 mg, 0.156mmol). The mixture was hydrogenated at 26° C. for 3 h under a H₂atmosphere. Then the solution was filtered and concentrated to give theresidue. The crude material was purified by preparative HPLC(Instrument: Gilson GX281/Column: Gemini 150*25 mm*Sum/Mobile phase A:Water (0.05% ammonia solution)/Mobile phaseB:Acetonitrile/Gradient:52-82(B %)/Flowrate: 25 mL/min/Run time: 10 min)to yield a white solid ofN-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide(41.16 mg, 0.079 mmol, 50.6% yield). TLC (DCM/MeOH=10:1, R_(f)=0.4): ¹HNMR (400 MHz, CD₃OD) δ 7.56-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.38-7.29(m, 3H), 7.24 (d, J=2.2 Hz, 1H), 6.96 (s, 1H), 4.19-4.09 (m, 4H), 3.80(s, 2H), 2.81 (t, J=5.3 Hz, 2H), 2.36 (s, 6H), 1.47 (t, J=6.9 Hz, 3H).ES-LCMS m/z 522 (M+H).

Biological Assays

The compound of the present invention was tested for RET kinaseinhibitory activity in a RET kinase enzyme assay, a cell-basedmechanistic assay and a cell-based proliferation assay.

RET Kinase Enzymatic Assay

Human RET kinase cytoplasmic domain (amino acids 658-1114 of accessionnumber NP 000314.1) was expressed as an N-terminal GST-fusion proteinusing a baculovirus expression system. GST-RET was purified usingglutathione sepharose chromatography. The RET kinase enzymatic assay wasperformed in a total volume of 10 uL with increasing concentrations ofRET kinase inhibitor as a singlet in a 384 well format as follows: RETinhibitor compound plates are prepared by adding 100 nL of RET inhibitorat different concentrations to a 384-well plate. 5 4/well of a 2× enzymemix (50 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); 1mM CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate);0.1 mg/mL BSA (bovine serum albumin); 1 mM DTT (dithiothreitol); 0.2 nMRET kinase) was added to the 384-well plate and incubated for 30 minutesat 23° C. 5 μL/well of a 2× substrate mix (50 mM HEPES; 1 mM CHAPS; 0.1mg/mL BSA; 20 μM adenosine triphosphate; 20 mM MgCl₂ and 1 biotinylatedpeptide substrate) was added and incubated for 1 hour at 23° C. 104/well of 2× stop/detection mix (50 mM HEPES; 0.1% BSA; 800 mM PotassiumFluoride; 50 mM EDTA (Ethylenediaminetetraacetic acid); 200× dilution ofEuropium Cryptate labeled anti-phosphotyrosine antibody; 62.5 nMStreptavidin-XL665) incubated for 1 hour at 23° C. and read on aHomogenous Time-Resolved Fluorescence reader. IC₅₀s were fitted usingGraphPad Prism to a sigmoidal dose response.

RET Kinase Cell-Based Mechanistic Assay

The potency of the compound of the invention was tested for its abilityto inhibit constitutive RET kinase phosphorylation in cell-based assay.TT cells (ATCC CRL-1803), a medullary thyroid cancer cell line withconstitutively activated RET kinase, were maintained in 150 cm² dishesin F12 Kaighn's medium, 10% fetal bovine serum, 1× Glutamax, 1×non-essential amino acids, 1× Pen/Strep antibiotics at 37° C. in 5%carbon dioxide. 1.0E5 TT cells/well were plated in a 96-well cellculture plate and allowed to adhere overnight. TT cells were treatedwith different concentrations of RET inhibitor compounds for 2 h at 37°C. in 5% carbon dioxide, washed with ice cold PBS (phosphate bufferedsaline) and lysed by adding 200 μL, of 25 mM Tris HCl pH 7.5; 2 mM EDTA;150 mM NaCl; 1% sodium deoxycholate; 1% Triton X-100; 50 mM sodium betaglycerophosphate; 1 mM sodium orthovanadate; 1× phosphatase inhibitorcocktail #2 (Sigma #P5726); 1× phosphatase inhibitor cocktail #3 (Sigma#P0044) and 1× complete mini EDTA free protease inhibitor cocktail(Roche #4693159001), incubation at −80° C. for 10 minutes and thawed onice. 100 μL, of TT cell lysate was added to a 96-well plate overnight at4° C. that had been coated overnight at 4° C. with 1:1,000 dilution of arabbit anti-RET antibody (Cell Signaling #7032) blocked with 1×PBS;0.05% Tween-20; 1% bovine serum albumin. Plates were washed 4× with 200μL, of 1×PBS; 0.05% Tween-20 and then 100 μL, of a 1:1,000 dilution ofan anti-phosphotyrosine detection antibody (Cell Signaling #7034) wasadded and incubated for 1 hour at 37° C. Plates were washed 4× with 200μL, of 1×PBS; 0.05% Tween-20 and then 100 μL, of a 1:1,000 dilution ofan anti-mouse immunoglobulin horse radish peroxidase conjugate antibody(Cell Signaling #7034) was added and incubated for 30 minutes at 37° C.Plates were washed 4× with 200 μL, of 1×PBS; 0.05% Tween-20, 100 μL, ofTMB (3,3′,5,5″-tetramethylbenzidine) substrate (Cell Signaling #7004)was added, incubated for 10 minutes at 37° C., 100 μL, of Stop solution(Cell Signaling #7002) was added and absorbance read on aspectrophotometer at 450 nm. IC₅₀s were fitted using GraphPad Prism to asigmoidal dose response.

RET Kinase Cell-Based Proliferation Assay

The potency of the compound of the invention was tested for its abilityto inhibit cell proliferation and cell viability. TT cells (ATCCCRL-1803), a medullary thyroid cancer cell line with constitutivelyactivated RET kinase, were maintained in 150 cm² dishes in F12 Kaighn'smedium, 10% fetal bovine serum, 1× Glutamax, 1× non-essential aminoacids, 1× Pen/Strep antibiotics at 37° C. in 5% carbon dioxide. 6.0E3 TTcells/well in 50 μL, of media were added to a 96-well cell culture plateand allowed to adhere overnight. 50 μL, of serially diluted RETinhibitor compounds were added to 96-well plate containing cultured TTcells and incubated at at 37° C. in 5% carbon dioxide for eight days. 50μL of CellTiter-Glo (Promega #G-7573) was added, contents mixed for 1minute on shaker followed by 10 minutes in the dark at 23° C. and theluminescence read by EnVision (PerkinElmer). IC₅₀s were fitted usingGraphPad Prism to a sigmoidal dose response.

Biological Data

Exemplified compounds of the present invention were tested in one ormore RET assays described above and were found to be inhibitors of RETwith IC₅₀<10 μM. Data for specific examples tested in the human RETkinase enzymatic assays are listed below in Table 2 as follows: +=10μM>IC₅₀≧500 nM; ++=500 nM≧IC₅₀≧100 nM; +++=IC₅₀<100 nM. Data forspecific examples tested in the human RET kinase cell-based mechanisticassay are listed below in Table 3 as follows: +=10 μM>IC₅₀>500 nM;++=500 nM≧IC₅₀≧100 nM; +++=IC₅₀≦100 nM; ND=Not Determined. Data forspecific examples tested in the human RET kinase cell-basedproliferation assay are listed below in Table 4 as follows: +=10μM>IC₅₀>500 nM; ++=500 nM≧IC₅₀>100 nM; +++=IC₅₀≦100 nM; ND=NotDetermined.

TABLE 2 Example # RET IC₅₀ 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++ 8+++ 9 +++ 10 ++ 11 +++ 12 +++ 13 +++ 14 + 15 +++ 16 +++ 17 +++ 18 ++ 19+++ 20 +++ 21 +++ 22 + 23 ++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40+++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++

TABLE 3 Example # RET IC₅₀ 1 ++ 2 +++ 3 +++ 4 ++ 5 +++ 6 +++ 7 ++ 8 ++ 9++ 10 + 11 +++ 12 +++ 13 ++ 14 ND 15 + 16 ++ 17 +++ 18 + 19 +++ 20 +++21 +++ 22 ND 23 + 24 ++ 25 ++ 26 ++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++32 +++ 33 ++ 34 ++ 35 +++ 36 +++ 37 ++ 38 ++ 39 +++ 40 +++ 41 +++ 42 +++43 +++ 44 ND 45 +++ 46 +++

TABLE 4 Example # RET IC₅₀ 1 ++ 2 ++ 3 +++ 4 ++ 5 +++ 6 +++ 7 ++ 8 + 9++ 10 + 11 ++ 12 ++ 13 ++ 14 ND 15 + 16 +++ 17 ++ 18 + 19 +++ 20 ++ 21+++ 22 ND 23 + 24 + 25 + 26 + 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++33 ++ 34 ++ 35 ++ 36 ++ 37 + 38 ++ 39 ++ 40 +++ 41 ++ 42 +++ 43 +++ 44ND 45 ++ 46 +++

In Vivo Colonic Hypersensitivity Model

The efficacy of RET kinase inhibitor compounds can be evaluated in an invivo model of colonic hypersensitivity (Hoffman, J. M., et al.,Gastroenterology, 2012, 142:844-854).

1-22. (canceled)
 23. A compound which is:

or a pharmaceutically acceptable salt thereof.
 24. A compound which is:


25. A pharmaceutical composition comprising the compound orpharmaceutically acceptable salt according to claim 23 and apharmaceutically acceptable excipient.
 26. A pharmaceutical compositioncomprising the compound according to claim 24 and a pharmaceuticallyacceptable excipient.